3,4-diarylpyrazoles as protein kinase inhibitors

ABSTRACT

3,4-diarylpyrazole derivatives of formula (I) as defined in the specification, and pharmaceutically acceptable salts thereof, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

The present invention relates to certain substituted 3,4-diarylpyrazolecompounds, which modulate the activity of protein kinases. The compoundsof this invention are therefore useful in treating diseases caused byderegulated protein kinase activity. The present invention also providesmethods for preparing these compounds, pharmaceutical compositionscomprising these compounds, and methods of treating diseases utilizingpharmaceutical compositions comprising these compounds.

The classical Ras, Raf, MEK (mitogen activated proteinkinase/extracellular signal-regulated kinase kinase), ERK (extracellularsignal-regulated kinase) pathway plays a central role in the regulationof a variety of cellular functions dependent upon cellular context,including cellular proliferation, differentiation, survival,immortalization and angiogenesis (reviewed in Peyssonnaux and Eychene,Biology of the Cell, 2001, 93, 3-62). In this pathway, Raf familymembers are recruited to the plasma membrane upon binding to guanosinetriphosphate (GTP) loaded Ras resulting in the phosphorylation andactivation of Raf proteins. Activated Rafs then phosphorylate andactivate MEKs, which in turn phosphorylate and activate ERKs. Uponactivation, ERKs translocate from the cytoplasm to the nucleus resultingin the phosphorylation and regulation of activity of transcriptionfactors such as Elk-I and Myc. The Ras/Raf/MEK/ERK pathway has beenreported to contribute to the tumorigenic phenotype by inducingimmortalisation, growth factor-independent growth, insensitivity togrowth-inhibitory signals, ability to invade and metastasize, bystimulating angiogenesis and by inhibiting apoptosis (reviewed in Kolchet al., Exp. Rev. Mol. Med., 2002, 25 April,http://www.expertreviews.org/02004386h.htm). In fact, ERKphosphorylation is enhanced in approximately 30% of all human tumours(Hoshino et al., Oncogene, 1999, 18, 813-822). This may be a result ofoverexpression and/or mutation of key members of the pathway.

Three Raf serine/threonine protein kinase isoforms have been reportedRaf-1/c-Raf, B-Raf and A-Raf (reviewed in Mercer and Pritchard, Biochim.Biophys. Acta, 2003, 1653, 25-40), the genes for which are thought tohave arisen from gene duplication. All three Raf genes are expressed inmost tissues but with differences: c-Raf is expressed ubiquitously athigh levels, whereas B-Raf high-level expression is found in neuronaltissue and A-Raf in urogenital tissue. The highly homologous Raf familymembers have overlapping but distinct biochemical activities andbiological functions (Hagemann and Rapp, Expt. Cell Res. 1999, 253,34-46). Expression of all three Raf genes is required for normal murinedevelopment however both c-Raf and B-Raf are required to completegestation. B-Raf −/− mice die at E12.5 due to vascular haemorrhagingcaused by increased apoptosis of endothelial cells (Wojnowski et al,Nature Genet., 1997, 16, 293-297). B-Raf is reportedly the major isoforminvolved in cell proliferation and the primary target of oncogenic Ras.Activating 5 somatic missense mutations have been identified exclusivelyfor B-Raf, occurring with a frequency of 66% in malignant cutaneousmelanomas (Davies et al., Nature, 2002, 417, 949-954) and also presentin a wide range of human cancers, including but not limited to papillarythyroid tumours (Cohen et al., J. Natl. Cancer Inst., 2003, 95,625-627), cholangiocarcinomas (Tannapfel et al., Gut, 2003, 52,706-712), colon and ovarian cancers (Davies et al., Nature, 10 2002,417, 949-954). The most frequent mutation in B-Raf (80%) is a glutamicacid for valine substitution at position 600. These mutations increasethe basal kinase activity of B-Raf and are thought to uncoupleRaf/MEK/ERK signalling from upstream proliferation drives including Rasand growth factor receptor activation resulting in constitutiveactivation of ERK. Mutated B-Raf proteins are transforming in NIH3T3cells (Davies et al., Nature, 2002, 15 417, 949-954) and melanocytes(Wellbrock et al., Cancer Res., 2004, 64, 2338-2342) and have also beenshown to be essential for melanoma cell viability and transformation(Hingorani et al., Cancer Res., 2003, 63, 5198-5202). As a key driver ofthe Raf/MEK/ERK signalling cascade, B-Raf represents a likely point ofintervention in tumours dependent on this pathway

Substituted pyrazole derivatives for the treatment of cytokine-mediateddiseases such as inflammation and arthritis are disclosed in WO98/52940and WO00/31063 in the name of G.D. Searle & Co.

Hydroxyaryl-pyrazole derivatives for the treatment of cancer aredisclosed in WO03/055860 in the name of Cancer Research Institute and inWO07/105,058 in the name of Pfizer Inc.

Pyrimidinyl-pyrazole derivatives for the treatment of hyperproliferativedisorders such as cancer are disclosed in WO07/24843 in the name ofSmithKline Beecham Corporation. Despite these developments, there isstill need for effective agents for said diseases.

The present inventors have now discovered that compounds of formula (I),described below, are kinase inhibitors and are thus useful in therapy asantitumor agents.

Accordingly, a first object of the present invention is to provide asubstituted 3,4-diarylpyrazole compound represented by formula (I),

wherein:m is an integer from 0 to 6;R1 is hydrogen, trichloromethyl, trifluoromethyl, halogen, cyano, OH,OR8, NR9R10,NR21COR22, COOH, COOR11, CONR12R13, or a group optionally substitutedselected from straight or branched (C₁-C₈) alkyl, (C₂-C₈) alkenyl or(C₂-C₈) alkynyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkenyl, heterocyclyl,aryl and heteroaryl, wherein:

-   -   R8 and R11 are each independently a group optionally substituted        selected from straight or branched (C₁-C₈) alkyl, (C₃-C₈)        cycloalkyl, heterocyclyl, aryl and heteroaryl;    -   R9, R10, R12 and R13 the same or different, are each        independently hydrogen or a group optionally substituted        selected from straight or branched (C₁-C₈) alkyl, (C₃-C₈)        cycloalkyl, heterocyclyl, aryl and heteroaryl, or taken together        with the nitrogen atom to which they are bonded either R9 and        R10 as well as R12 and R13 may form an optionally substituted        heterocyclyl or heteroaryl, optionally containing one additional        heteroatom or heteroatomic group selected from S, O, N or NH;    -   R21 and R22 the same or different, are each independently        hydrogen or a group optionally substituted selected from        straight or branched (C₁-C₈) alkyl, (C₃-C₈) cycloalkyl,        heterocyclyl, aryl and heteroaryl, or taken together with the        atoms to which they are bonded R21 and R22 may form an        optionally substituted heterocyclyl, optionally containing one        additional heteroatom or heteroatomic group selected from S, O,        N or NH;

X is —CH or N;

R2 is hydrogen, halogen, NR14R15, SR23 or SO₂R23, wherein:

-   -   R14 and R15 are independently hydrogen or a group optionally        substituted selected from straight or branched (C₁-C₈) alkyl,        (C₃-C₈) cycloalkyl, heterocyclyl, aryl and heteroaryl; or taken        together with the nitrogen atom to which they are bonded R14 and        R15 may form an optionally substituted 3 to 8 membered        heterocyclyl or heteroaryl, optionally containing one additional        heteroatom or heteroatomic group selected from S, O, N or NH; or        R14 is hydrogen and R15 is COR16,    -   wherein:        -   R16 is OR17, NR18R19 or a group optionally substituted            selected from straight or branched (C₁-C₈) alkyl, (C₂-C₈)            alkenyl or (C₂-C₈) alkynyl, (C₃-C₈) cycloalkyl, (C₃-C₈)            cylcoalkenyl, heterocyclyl, aryl and heteroaryl, wherein:            -   R17 is a group optionally substituted selected from                straight or branched (C₁-C₈) alkyl, (C₃-C₈) cycloalkyl,                heterocyclyl, aryl and heteroaryl;            -   R18 and R19 are each independently a group optionally                substituted selected from straight or branched (C₁-C₈)                alkyl, (C₃-C₈) cycloalkyl, heterocyclyl, aryl and                heteroaryl, or taken together with the nitrogen atom to                which they are bonded R18 and R19 may form an optionally                substituted 3 to 8 membered heterocyclyl or heteroaryl,                optionally containing one additional heteroatom or                heteroatomic group selected from S, O, N or NH;    -   R23 is a group optionally substituted selected from straight or        branched (C₁-C₈) alkyl, (C₃-C₈) cycloalkyl, heterocyclyl, aryl        and heteroaryl,        R3, R4, R5 and R6 are each independently hydrogen, halogen,        trifluoromethyl, trichloromethyl, cyano, OR20 or a group        optionally substituted selected from straight or branched        (C₁-C₈) alkyl, and (C₃-C₈) cycloalkyl, wherein:    -   R20 is a group optionally substituted selected from straight or        branched (C₁-C₈) alkyl and (C₃-C₈) cycloalkyl;        A is —CON(Y), —CON(Y)O—, —CON(Y)N(Y)—, —CON(Y)SO₂—, —SO₂N(Y)—,        —SO₂N(Y)O—, —SO₂N(Y)N(Y)—, —SO₂N(Y)CO—, —SO₂N(Y)CON(Y)—,        —SO₂N(Y)SO₂—, —N(Y)CO—, —N(Y)SO₂—, —N(Y)CON(Y)—, —N(Y)CSN(Y)—,        —N(Y)CON(Y)N(Y)—, —N(Y)COO—, —N(Y)CON(Y)SO₂—, —N(Y)SO₂N(Y)—,        —C(R′R″)CON(Y)—, —C(R′R″)CSN(Y)—, —C(R′R″)CON(Y)O—,        —C(R′R″)CON(Y)N(Y)—, —C(R′R″)CON(Y)SO₂—, —C(R′R″)SO₂N(Y)—,        —C(R′R″)SO₂N(Y)O—, —C(R′R″)SO₂N(Y)N(Y)—, —C(R′R″)SO₂N(Y)CO—,        —C(R′R″)SO₂N(Y)SO₂—, —C(R′R″)N(Y)CO, —C(R′R″)N(Y)SO₂—,        —C(R′R″)N(Y)CON(Y)—, —C(R′R″)N(Y)CSN(Y)—, —C(R′R″)N(Y)COO—,        —C(R′R″)N(Y)SO₂N(Y)— or —N(Y)C(R′R″)—, wherein:    -   Y is hydrogen or an optionally substituted straight or branched        (C₁-C₃) alkyl;    -   and R′ and R″ are independently hydrogen or an optionally        further substituted straight or branched (C₁-C₆) alkyl, or taken        together with the carbon atom to which they are bonded R′ and R″        may form an optionally substituted (C₃-C₈) cycloalkyl;        R7 is hydrogen or an optionally substituted group selected from        straight or branched (C₁-C₈) alkyl, (C₂-C₈) alkenyl, or (C₃-C₈)        cycloalkyl, (C₂-C₈) alkynyl, (C₃-C₈) cylcoalkenyl, heterocyclyl,        aryl and heteroaryl;        and pharmaceutically acceptable salts thereof.

The present invention also provides methods of preparing the substituted3,4-diarylpyrazole compounds, represented by formula (I), preparedthrough a process consisting of standard synthetic transformations.

The present invention also provides a method for treating diseasescaused by and/or associated with deregulated protein kinase activity,particularly the RAF family, PLK family, protein kinase C in differentisoforms, Met, PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora A, Aurora B,Aurora C, Bub-1, Chk1, Chk2, HER2, MEK1, MAPK, EGF-R, PDGF-R, FGF-R,IGF-R, PI3K, weel kinase, Src, Abl, Akt, MAPK, ILK, MK-2, IKK-2, Cdc7,Nek, Cdk/cyclin kinase family, more particularly the RAF family, whichcomprises administering to a mammal, in need thereof, an effectiveamount of a substituted 3,4-diarylpyrazole compound represented byformula (I) as defined above.

A preferred method of the present invention is to treat a disease causedby and/or associated with deregulated protein kinase activity selectedfrom the group consisting of cancer, cell proliferative disorders, viralinfections, autoimmune and neurodegenerative disorders.

Another preferred method of the present invention is to treat specifictypes of cancer including but not limited to: carcinoma such as bladder,breast, colon, kidney, liver, lung, including small cell lung cancer,esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid,prostate, and skin, including squamous cell carcinoma; hematopoietictumors of lymphoid lineage including leukaemia, acute lymphociticleukaemia, acute lymphoblastic leukaemia, B-cell lymphoma,T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy celllymphoma and Burkett's lymphoma; hematopoietic tumors of myeloidlineage, including acute and chronic myelogenous leukemias,myelodysplastic syndrome and promyelocytic leukaemia; tumors ofmesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumorsof the central and peripheral nervous system, including astrocytomaneuroblastoma, glioma and schwannomas; other tumors, including melanoma,seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum,keratoxanthoma, thyroid follicular cancer and Kaposi's sarcoma.

Another preferred method of the present invention is to treat specificcellular proliferation disorders such as, for example, benign prostatehyperplasia, familial adenomatosis polyposis, neurofibromatosis,psoriasis, vascular smooth cell proliferation associated withatherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis andpost-surgical stenosis and restenosis.

Another preferred method of the present invention is to treat viralinfections, in particular the prevention of AIDS development inHIV-infected individuals.

In addition, the method of the present invention also provides tumorangiogenesis and metastasis inhibition as well as the treatment of organtransplant rejection and host versus graft disease.

In a further preferred embodiment, the method of the present inventionfurther comprises subjecting the mammal in need thereof to a radiationtherapy or chemotherapy regimen in combination with at least onecytostatic or cytotoxic agent.

Moreover the invention provides an in vitro method for inhibiting theRAF family protein activity which comprises contacting the said proteinwith an effective amount of a compound of formula (I).

The present invention also provides a pharmaceutical compositioncomprising one or more compounds of formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable excipient,carrier or diluent.

The present invention further provides a pharmaceutical compositioncomprising a compound of formula (I) in combination with knownanticancer treatments such as radiation therapy or chemotherapy regimenin combination with cytostatic or cytotoxic agents, antibiotic-typeagents, alkylating agents, antimetabolite agents, hormonal agents,immunological agents, interferon-type agents, cyclooxygenase inhibitors(e.g. COX-2 inhibitors), matrixmetalloprotease inhibitors, telomeraseinhibitors, tyrosine kinase inhibitors, anti-growth factor receptoragents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents(e.g. angiogenesis inhibitors), farnesyl transferase inhibitors, ras-rafsignal transduction pathway inhibitors, cell cycle inhibitors, othercdks inhibitors, tubulin binding agents, topoisomerase I inhibitors,topoisomerase II inhibitors, and the like. Additionally, the inventionprovides a product or kit comprising a compound of formula (I) or apharmaceutically acceptable salt thereof, as defined above, orpharmaceutical compositions thereof and one or more chemotherapeuticagents, as a combined preparation for simultaneous, separate orsequential use in anticancer therapy.

In yet another aspect the invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof, as defined above, for useas a medicament.

Moreover the invention provides the use of a compound of formula (I) ora pharmaceutically acceptable salt thereof, as defined above, in themanufacture of a medicament with antitumor activity.

Finally, the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof, as defined above, for use in amethod of treating cancer.

Unless otherwise specified, when referring to the compounds of formula(I) per se as well as to any pharmaceutical composition thereof or toany therapeutic treatment comprising them, the present inventionincludes all of the isomers, tautomers, hydrates, solvates, complexes,metabolites, prodrugs, carriers, N-oxides and pharmaceuticallyacceptable salts of the compounds of this invention.

A metabolite of a compound of formula (I) is any compound into whichthis same compound of formula (I) is converted in vivo, for instanceupon administration to a mammal in need thereof. Typically, withouthowever representing a limiting example, upon administration of acompound of formula (I), this same derivative may be converted into avariety of compounds, for instance including more soluble derivativeslike hydroxylated derivatives, which are easily excreted. Hence,depending upon the metabolic pathway thus occurring, any of thesehydroxylated derivatives may be regarded as a metabolite of thecompounds of formula (I). Prodrugs are any covalently bonded compounds,which release in vivo the active parent drug according to formula (I).

N-oxides are compounds of formula (I) wherein nitrogen and oxygen aretethered through a dative bond.

If a chiral center or another form of an isomeric center is present in acompound of the present invention, all forms of such isomer or isomers,including enantiomers and diastereomers, are intended to be coveredherein. Compounds containing a chiral center may be used as a racemicmixture, an enantiomerically enriched mixture, or the racemic mixturemay be separated using well-known techniques and an individualenantiomer may be used alone. In cases in which compounds haveunsaturated carbon-carbon double bonds, both the cis (Z) and trans (E)isomers are within the scope of this invention.

In cases when compounds can exist in tautomeric forms, each form iscontemplated as being included within this invention whether existing inequilibrium or predominantly in one form.

As such, unless otherwise provided, when in compounds of formula (I) mis 0 and R1 is hydrogen, only one of the following tautomeric forms offormula (Ia) or (Ib) is indicated, the remaining one has still to beintended as comprised within the scope of the invention:

In cases wherein compounds may exist in other tautomeric forms, such asketo-enol tautomers, each tautomeric form is contemplated as beingincluded within this invention whether existing in equilibrium orpredominantly in one form.

With the term “straight or branched C₁-C₈ alkyl”, we intend any of thegroups such as, for instance, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl,n-octyl and the like.

With the term “straight or branched C₁-C₆ alkyl”, we intend any of thegroups such as, for instance, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, and thelike.

With the term “straight or branched C₁-C₃ alkyl”, we intend any of thegroups such as, for instance, methyl, ethyl, n-propyl, isopropyl.

With the term “C₃-C₈ cycloalkyl” we intend, unless otherwise provided,3- to 8-membered all-carbon monocyclic ring, which may contain one ormore double bonds but does not have a completely conjugated π-electronsystem. Examples of cycloalkyl groups, without limitation, arecyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexene and cyclohexadiene.

With the term “heterocyclyl” we intend a 3- to 8-membered, saturated orpartially unsaturated carbocyclic ring where one or more carbon atomsare replaced by heteroatoms such as nitrogen, oxygen and sulfur. Nonlimiting examples of heterocyclyl groups are, for instance, pyrane,pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine,pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran,1,3-dioxolane, piperidine, piperazine, morpholine and the like.

With the term “C₂-C₈ alkenyl” we intend an aliphatic C₂-C₈ hydrocarbonchain containing at least one carbon-carbon double bond and which can bestraight or branched. Representative examples include, but are notlimited to, ethenyl, 1-propenyl, 2-propenyl, 1- or 2-butenyl, and thelike.

With the term “C₂-C₈ alkynyl” we intend an aliphatic C₂-C₈ hydrocarbonchain containing at least one carbon-carbon triple bond and which can bestraight or branched. Representative examples include, but are notlimited to, ethynyl, 1-propynyl, 2-propynyl, 1- or 2-butynyl, and thelike.

The term “aryl” refers to a mono-, bi- or poly-carbocyclic hydrocarbonwith from 1 to 4 ring systems, optionally further fused or linked toeach other by single bonds, wherein at least one of the carbocyclicrings is “aromatic”, wherein the term “aromatic” refers to completelyconjugatedπ-electron bond system. Non-limiting examples of such arylgroups are phenyl, α- or β-naphthyl or biphenyl groups.

The term “heteroaryl” refers to aromatic heterocyclic rings, typically5- to 8-membered heterocycles with from 1 to 3 heteroatoms selectedamong N, O or S; the heteroaryl ring can be optionally further fused orlinked to aromatic and non-aromatic carbocyclic and heterocyclic rings.Not limiting examples of such heteroaryl groups are, for instance,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl,thiazolyl, isothiazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl,oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl, isoindolinyl,benzoimidazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl,1-phenyl-1,2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothiophenyl; benzopyranyl, 2,3-dihydrobenzoxazinyl,2,3-dihydroquinoxalinyl and the like.

According to the present invention and unless otherwise provided, any ofthe above R1, R2, R3, R4, R5, R6 and R7 group may be optionallysubstituted, in any of their free positions, by one or more groups, forinstance 1 to 6 groups, independently selected from: halogen, nitro, oxogroups (═O), cyano, C₁-C₈ alkyl, polyfluorinated alkyl, polyfluorinatedalkoxy, C₂-C₈ alkenyl, C₂-C₈ alkynyl, hydroxyalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, C₃-C₈cycloalkyl, hydroxy, alkoxy, aryloxy, heterocyclyloxy, methylenedioxy,alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy,heterocyclylcarbonyloxy, alkylideneaminooxy, carboxy, alkoxycarbonyl,aryloxycarbonyl, cycloalkyloxycarbonyl,heterocyclylalkyloxycarbonyl-amino, ureido, alkylamino, dialkylamino,arylamino, diarylamino, heterocyclylamino, formylamino,alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino,hydroxyaminocarbonyl alkoxyimino, alkylsulfonylamino, arylsulfonylamino,heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl,cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio,phosphonate and alkylphosphonate. In their turn, whenever appropriate,each of the above substituent may be further substituted by one or moreof the aforementioned groups.

With the term halogen atom we intend a fluorine, chlorine, bromine oriodine atom.

With the term cyano we intend a —CN residue.

With the term nitro we intend a —NO₂ group.

With the term polyfluorinated alkyl or polyfluorinated alkoxy we intendany of the above straight or branched C₁-C₈ alkyl or alkoxy groups whichare substituted by more than one fluorine atom such as, for instance,trifluoromethyl, trifluoroethyl, 1,1,1,3,3,3-hexafluoropropyl,trifluoromethoxy and the like.

With the term hydroxyalkyl we intend any of the above C₁-C₈ alkyl,bearing an hydroxyl group such as, for instance, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl and the like.

From all of the above, it is clear to the skilled person that any groupwhich name is a composite name such as, for instance, arylamino has tobe intended as conventionally construed by the parts from which itderives, e.g. by an amino group which is further substituted by aryl,wherein aryl is as above defined.

Likewise, any of the terms such as, for instance, alkylthio, alkylamino,dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl,heterocyclylcarbonylamino, cycloalkyloxycarbonyl and the like, includegroups wherein the alkyl, alkoxy, aryl, C₃-C₈ cycloalkyl andheterocyclyl moieties are as above defined.

Pharmaceutically acceptable salts of the compounds of formula (I)include the acid addition salts with inorganic or organic acids, e.g.,nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric,acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, fumaric,malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic,methanesulphonic, isethionic and salicylic acid.

Pharmaceutically acceptable salts of the compounds of formula (I) alsoinclude the salts with inorganic or organic bases, e.g., alkali oralkaline-earth metals, especially sodium, potassium, calcium ammonium ormagnesium hydroxides, carbonates or bicarbonates, acyclic or cyclicamines, preferably methylamine, ethylamine, diethylamine, triethylamine,piperidine and the like.

A preferred class of compounds of formula (I) are the compounds wherein:

m is an integer from 0 to 2.

Another preferred class of compounds of formula (I) are the compoundswherein:

A is —CON(Y), —CON(Y)O—, —CON(Y)N(Y)—, —CON(Y)SO₂—, —SO₂N(Y)—, —N(Y)CO—,—N(Y)SO₂—, —N(Y)CON(Y)—, —N(Y)CSN(Y)—, —N(Y)COO—, —C(R′R″)CON(Y)—,—C(R′R″)N(Y)CO, —C(R′R″)N(Y)CON(Y)—,wherein:Y and R′ and R″ are as defined above.

A further preferred class of compounds of formula (I) are the compoundswherein:

R1 is hydrogen, trichloromethyl, trifluoromethyl, halogen, cyano, OH,OR8, NR9R10, CONR12R13, or a group optionally substituted selected fromstraight or branched (C₁-C₈) alkyl, (C₂-C₈) alkenyl or (C₂-C₈) alkynyl,(C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkenyl, heterocyclyl, aryl andheteroaryl, wherein:

R8, R9, R10, R12 and R13 are as defined above.

A particularly preferred class of compounds of formula (I) are thecompounds wherein:

R1 is hydrogen, trichloromethyl, trifluoromethyl, halogen and cyano.

Another further preferred class of compounds of formula (I) are thecompounds wherein:

R2 is hydrogen or NR14R15, wherein:R14 and R15 are independently hydrogen or a group optionally substitutedselected from straight or branched (C₁-C₈) alkyl, (C₃-C₈) cycloalkyl,heterocyclyl, aryl and heteroaryl.

Another further preferred class of compounds of formula (I) are thecompounds wherein:

R3, R4, R5 and R6 are each independently hydrogen, halogen,trifluoromethyl, trichloromethyl or cyano.

Another further preferred class of compounds of formula (I) are thecompounds wherein:

R7 is an optionally substituted group selected from straight or branched(C₁-C₈) alkyl, (C₃-C₈) cylcoalkyl, (C₃-C₈) cycloalkenyl, heterocyclyl,aryl and heteroaryl.

Preferred specific compounds of formula (I) are the compounds listedbelow:

-   1)    1-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,-   2)    2,5-difluoro-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide,-   3) N-(4-chloro-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide,-   4)    N-(4-tert-Butyl-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide,-   5)    1-(4-chloro-3-trifluoromethyl-phenyl)-3-{3-[1-(2-fluoro-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-urea,-   6) furan-2-sulfonic acid    [3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,-   7) thiophene-3-sulfonic acid    [3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,-   8) 1-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-p-tolyl-urea,-   9)    1-(4-chloro-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea,-   10)    1-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,-   11)    1-[3-(1-cyanomethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,-   12)    1-{3-[4-(2-amino-pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}-3-(4-trifluoromethyl-phenyl)-urea,-   13)    1-{3-[1-(2-fluoro-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-3-(4-trifluoromethyl-phenyl)-urea,-   14)    1-{3-[1-(2-hydroxy-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-3-(4-trifluoromethyl-phenyl)-urea,-   15)    1-[3-(1-piperidin-4-yl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,-   16)    N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2-(4-trifluoromethyl-phenyl)-acetamide,-   17)    N-[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyridin-2-yl]-acetamide,-   18)    N-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-benzenesulfonamide,-   19) thiophene-3-sulfonic acid    [2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,-   20) furan-2-sulfonic acid    [2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,-   21) propane-1-sulfonic acid    [2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,-   22)    1-(4-tert-butyl-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea,-   23)    1-[4-(cyano-dimethyl-methyl)-phenyl]-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea,-   24)    1-[2-ffluoro-5-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,-   25)    1-(2-fluoro-4-trifluoromethyl-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea,-   26) cyclopropanesulfonic acid    [2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,-   27) 2,2,2-trifluoro-ethanesulfonic acid    [2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,-   28)    N-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide,-   29) cyclohexanesulfonic acid    [2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,-   30)    1-[3-(4-pyrimidin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,-   31)    1-{3-[4-(2-amino-pyrimidin-4-yl)-1H-pyrazol-3-yl]-phenyl}-3-(4-trifluoromethyl-phenyl)-urea,-   32)    N-[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyrimidin-2-yl]-acetamide,-   33)    2,5-difluoro-N-[3-(4-pyrimidin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide,-   34)    N-{3-[4-(2-amino-pyrimidin-4-yl)-1H-pyrazol-3-yl]-phenyl}-2,5-difluoro-benzenesulfonamide,    to 35)    N-(4-{3-[3-(2,5-difluoro-benzenesulfonylamino)-phenyl]-1H-pyrazol-4-yl}-pyrimidin-2-yl)-acetamide,-   36)    N-[2,4-difluoro-3-(4-pyrimidin-4-yl-1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-benzenesulfonamide,-   37)    N-{3-[4-(2-amino-pyrimidin-4-yl)-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide,-   38)    N-(4-{3-[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-1H-pyrazol-4-yl}-pyrimidin-2-yl)-acetamide,-   39)    N-[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyridin-2-yl]-propionamide,-   40)    N-[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyridin-2-yl]-isobutyramide,-   41) cyclopentanecarboxylic acid    [4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyridin-2-yl]-amide,-   42)    2-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-N-(4-trifluoromethyl-phenyl)-acetamide,-   43)    4-hydroxy-N-[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyridin-2-yl]-butyramide,-   44)    N-(4-{3-[3-(2,5-difluoro-benzenesulfonylamino)-phenyl]-1H-pyrazol-4-yl}-pyridin-2-yl)-acetamide,-   45)    N-(4-{3-[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-1H-pyrazol-4-yl}-pyridin-2-yl)-acetamide,-   46)    3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-N-(4-trifluoromethyl-phenyl)-benzamide,-   47)    4-pyridin-4-yl-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazole-1-carboxylic    acid ethyl ester-   48)    1-[3-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,-   49)    1-[3-(1-butyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,-   50)    1-[3-(1-Isobutyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,-   51)    N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide,-   52)    N-[2,4-difluoro-3-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-benzenesulfonamide,-   53)    N-{2,4-difluoro-3-[4-(2-methylamino-pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}-2,5-difluoro-benzenesulfonamide,-   54)    N-{3-[4-(2-ethylamino-pyridin-4-yl)-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide,-   55)    N-{3-[4-(2-ethylamino-pyrimidin-4-yl)-1H-pyrazol-3-yl]-phenyl}-2,5-difluoro-benzenesulfonamide,-   56)    N-[2,4-difluoro-3-(1-isobutyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-benzenesulfonamide,-   57)    N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide,-   58)    N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide,-   59)    N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-4-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide,-   60)    N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide,-   61)    N-{3-[4-(2-amino-pyrimidin-4-yl)-1-ethyl-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide,-   62)    N-{2,4-difluoro-3-[1-(2-piperidin-1-yl-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-2,5-difluoro-benzenesulfonamide,-   63)    N-{2,4-difluoro-3-[1-(2-morpholin-4-yl-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-2,5-difluoro-benzenesulfonamide,-   64)    N-(2,4-difluoro-3-{1-[2-(4-methyl-piperazin-1-yl)-ethyl]-4-pyridin-4-yl-1H-pyrazol-3-yl}-phenyl)-2,5-difluoro-benzenesulfonamide,-   65)    N-{3-[1-(2-dimethylamino-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide,-   66)    (2,5-difluoro-benzyl)-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-amine,-   67)    4-{3-[3-(2,5-difluoro-benzyloxy)-2,6-difluoro-phenyl]-1-ethyl-1H-pyrazol-4-yl}-pyridine    and-   68)    N-{3-[4-(2-Amino-pyridin-4-yl)-1-ethyl-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide.

The present invention also provides a process for the preparation of acompound of formula (I) as defined above, by using the reaction routesand synthertic schemes described below, employing the techniquesavailable in the art and starting materials readily available. Thepreparation of certain embodiments of the present invention is describedin the examples that follow, but those of ordinary skill in the art willrecognize that the preparations described may be readily adapted toprepare other embodiments of the present invention. For example, thesynthesis on non-examplified compounds according to the invention may beperformed by modifications apparent to those skilled in the art, forinstance by appropriately protecting interfering groups, by changing toother suitable reagents known in the art, or by making routinemodifications of reaction conditions. Alternatively other reactionsreferred to herein or known in the art will be recognized as havingadaptability for preparing other compounds of the invention. Thereported Scheme 1 shows the preparation of a compound of formula (I).

whereinG is a suitable precursor of the A-R7 groups defined above, such as anoptionally protected amino group, a nitro group, a halogen, a cyanogroup or a suitable carboxylic ester; and X, m, R1, R2, R3, R4, R5, R6and R7 are as defined above.

The intermediate compound of formula (II) is prepared according tomethod A, B, C and D described below.

A compound of formula (II) can be optionally converted into anothercompound of formula (II) according to any of the methods E and Fdescribed below.

A compound of formula (I) is prepared following one of the syntheticmethods described hereafter in method G, H, I, J, and M.

A compound of formula (I) can be optionally converted into anothercompound of formula (I) according to any of the methods K and Ldescribed below.

All those with ordinary skills in the art will appreciate that anytransformation performed according to said methods may require standardmodifications such as, for instance, protection of interfering groups,change to other suitable reagents known in the art, or make routinemodifications of reaction conditions.

Method A

In the above scheme, X, m, R1, R2, R3, R4, R5, R6 and G are as definedabove, J is oxygen or a group —N(CH₃)O—, PG₁ is a protecting group suchas silyl or acyl derivatives or tetrahydropyranyl, Alk is C₁-C₆ alkyl, Eis hydrogen or alkoxycarbonyl, L is OH or a group that may work as aleaving group, such as a halogen atom, a tosylate, mesylate or triflate.

In a synthetic process for the preparation of a compound of formula(II), which is described in method A, in step “a” a compound of formula1 is reacted with a dialkylphosphite to yield a hydroxyalkyl phosphonateof formula 2. In steps “b” and “c” protection of the alcoholic functionfollowed by Wittig-type reaction with a suitable 4-pyridyl or4-pyrimidinyl carboxaldehyde of formula 4 yields a compound of formula 5that in step “d” is conveniently hydrolyzed to yield a ketonerepresented by formula 6. In step “e” the latter may be obtainedalternatively starting from a compound of formula 7 which is transformedin the corresponding metal anion and reacted with an aromatic alkylcarboxylate or Weinreb amide of formula 8. In step “f” transformation ofa compound of formula 6 to pyrazoles is accomplished by forming anenaminone derivative of formula 9, followed in step “g” and “g1” bycondensation with an appropriate hydrazine to give a compound of formula(II). With a substituted hydrazine the latter reaction yields a mixtureof regioisomers from which the desired isomer is purified by knownmethods such as silica gel chromatography or preparative HPLC. Whenhydrazine is used, a N-unsubstituted pyrazole of formula (II)A isobtained (m is 0 and R1 is hydrogen).

In the latter case in step “h” introduction of the —(CH₂)_(m)R1 group toform a compound of formula (II) is accomplished through N-alkylation ofa suitable alkylating agent L-(CH₂)_(m)R1, where L is a group that,optionally upon activation, may work as a leaving group. The latterreaction could yield a mixture of regioisomers from which the desiredisomer is purified by known methods such as silica gel chromatography orpreparative HPLC.

According to step “a” of method A, the condensation between an aromaticaldehyde of formula 1 with a dialkyl phosphite can be accomplished in avariety of ways according to conventional methods. Preferably it iscarried out in presence of a base, such as triethylamine (TEA)1,8-diazabicyclo[5.4.0]undec-7ene (DBU), lithium diisopropylamide (LDA),sodium methoxide or the like, preferably in a solvent such as, forinstance, ethylacetate, dichloromethane, toluene, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, acetonitrile at a temperature rangingfrom 0° C. to reflux and for a time ranging from 30 minutes to about 24hours.

According to step “b” of method A, the protection of the alcoholicfunction can be accomplished in a variety of ways according toconventional methods that can be readily appreciated by all thoseskilled in the art. For instance, such alcoholic group can be protectedas silyl derivatives by treatment with a suitable silylating agent, suchas any alkylsilyl halide or azide in the presence of a base, such as,for instance, 1,8-diazabicyclo[5.4.0]undec-7ene (DBU), or by treatmentwith 1,1,1,3,3,3-hexamethyldisilazane in the presence of submolaramounts of Iodine or of a suitable acid, such as, for instance,sulphuric acid. Such reactions can be performed using a variety ofsolvents such as dichloromethane, toluene, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, acetonitrile at a temperature ranging from 0° C. toreflux and for a time ranging from 30 minutes to about 24 hours. Again,said protection can be accomplished by acylation following treatmentwith a suitable acylating agent such as an acid chloride or anhydride inthe presence of a base using a variety of solvents such asdichloromethane, toluene, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide,acetonitrile or the like at a temperature ranging from 0° C. to refluxand for a time ranging from 30 minutes to about 24 hours. Morepreferably such a protection can be accomplished using3,4-dihydro-2H-pyran in the presence of a suitable acidic catalyst, suchas, for instance, p-Toluensulfonic acid (PTSA) using solvents such astoluene, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane at atemperature ranging from 0° C. to reflux and for a time ranging from 30minutes to about 24 hours.

According to step “c” of method A, the reaction of a compound of formula3 with a compound of formula 4 can be accomplished in the presence of asuitable base such as, for instance sodium methoxide, sodium ethoxide,sodium hydride, lithium diisopropylamide or triethylamine in a varietyof solvents such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,toluene, dichloromethane, or the like at a temperature ranging from 0°C. to reflux and for a time ranging from 30 minutes to about 24 hours.

According to step “d” of method A, the conversion of a compound offormula 5 to a compound of formula 6 can be accomplished in a variety ofways known in the art depending on the nature of the protecting groupitself. For example, when the protective group introduced in step “b” ofmethod A is tetrahydropyranyl, the conversion is made using any of thehydrolytic method known in the literature, for instance using an aqueoussolution of hydrochloric acid in a suitable co-solvent, for instancemethanol, ethanol, tetrahydrofuran, acetonitrile or the like at atemperature ranging from 0° C. to reflux and for a time ranging from 30minutes to about 24 hours. When, for example, such a protecting group isa silyl group, deprotection can be accomplished using strong acids liketrifluoroacetic acid, perchloric acid, hydrochloric acid, hydrofluoricacid, as well as tetrabutyl ammonium fluoride and derivatives thereof,in a suitable solvent such as tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, methanol, ethanol, acetonitrile, dichloromethane,or the like at a temperature ranging from 0° C. to reflux and for a timeranging from 30 minutes to about 24 hours. When, for example, such aprotecting group is an acyl group, deprotection can be accomplishedusing aqueous alkali, such as NaOH, KOH, LiOH or the like, optionally inthe presence of a suitable solvent such as ethanol, methanol,tetrahydrofuran or the like.

According to step “e” of method A, a compound of formula 7 is convertedto a compound of formula 6 by reaction with a strong base such as sodiumhexamethyldisilazane (NaHMDS), lithium hexamethyldisilazane (LiHMDS),lithium diisopropylamide (LDA), a Grignard reagent and the like,following condensation with an aromatic alkyl carboxylate or Weinrebamide of formula 8. Said reaction is typically performed using a varietyof solvents such as toluene, N,N-dimethylformamide, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, or the like at a temperature rangingfrom 0° C. to reflux and for a time ranging from 30 minutes to about 24hours.

According to step “f” of method A, the synthesis of the enaminonederivative of formula 9 is accomplished using a N,N-dimethylformamidedialkyl acetal, such as, for instance N,N-dimethylformamide dimethylacetal, N,N-dimethylformamide ditertbutyl acetal and the like in asuitable solvent such as tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, acetonitrile, N,N-dimethylformamide,N,N-dimethylacetamide, or the like at a temperature ranging from 0° C.to reflux and for a time ranging from 30 minutes to about 24 hours.

According to step “g” of method A, the conversion of a compound offormula 9 into a compound of formula (II) is accomplished by using ahydrazine derivative of formula NH₂NH—(CH₂)_(m)R1 in a suitable solventsuch as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methanol,ethanol, acetonitrile, acetic acid, N,N-dimethylformamide or mixturesthereof at a temperature ranging from 0° C. to reflux and for a timeranging from 30 minutes to about 24 hours. When hydrazine is used (m isO and R1 is hydrogen), the reaction proceeds according to step “g1” ofmethod A yielding a N-unsubstituted pyrazole of formula (II)A.

According to step “h” of method A, the conversion of saidN-unsubstituted pyrazole of formula (II)A in another compound of formula(II) can be accomplished using a compound of formula L-(CH₂)_(m)R1wherein L is OH, in which case the Mitsunobu conditions can be employed,or L is a group that optionally upon activation, may work as a leavinggroup, such as a halogen atom, a tosylate, mesylate or triflate.

In the former instance, that is, when a Mitsunobu protocol is employed,the reaction can be accomplished using a dialkyl azodicarboxylate, suchas diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD)or the like, in the presence of a trialkyl or triaryl phosphine,preferably triphenyl phosphine in a suitable solvent such astetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, acetonitrile. When Lis a halogen atom or a group such as tosylate, mesylate or triflate orthe like the conversion can be accomplished using a suitable base suchas, for instance, NaH, K₂CO₃, Cs₂CO₃, NaOH, DBU, LiHMDS and the like, ina suitable solvent such as dichloromethane, tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, isopropanol,acetonitrile, acetic acid, N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide and the like. Said reactions can be carried out attemperatures ranging from 0° C. to reflux and for a time ranging from 30minutes to about 48 hours. If required compounds of formula (II) can beseparated and purified by silica gel chromatography or preparative HPLC.

Method B

In the above scheme, X, m, R1, R2, R3, R4, R5, R6, G and L are asdefined above, L′ is a group that may work as a leaving group, such as ahalogen atom, a tosylate, mesylate or triflate, and PG₂ is a protectinggroup such as p-methoxybenzyl, tetrahydropyranyl, trityl or a silylderivative such as trimethylsilylethoxymethyl (SEM) and2-trimethylsilylethanesulfonyl (SES), and M is B(OH)₂, B(Oalk)₂,Sn(Alk)₃, Al(Alk)₂, ZnHal, MgHal or ZrCp₂Hal.

In another synthetic process for the preparation of a compound offormula (II), which is described in method B, in step “a” 4-picoline or4-methylpyrimidine derivative of formula 11 is reacted with phosphoryltrichloride under the Vilsmeier condition to form a malonaldehydederivative, which is condensed with hydroxylamine to form the isoxazolecompound of formula 12. In step “b” ring-opening of the isoxazolederivative yields a compound of formula 13, then in step “c” thecondensation with hydrazine yields the pyrazole derivative of formula14. In step “d” a Sandmeier reaction is used to convert a compound offormula 14 into a iodopyrazole derivative of formula 15. In step “e” thepyrazole nitrogen protection of a compound of formula 15 with a suitableprotecting group such as, for instance, p-methoxybenzyl,tetrahydropyranyl or trytyl yields an intermediate of formula 16. Instep “f” the latter can be transformed into a compound of formula 18 byexploiting any of the cross-coupling reactions suitable for theformation of carbon-carbon bonds. Said reactions, which are well knownin the art, imply coupling with a suitable organometal reagent, such as,for instance, an organoboron, organotin, organozinc, organoalluminum ororganozirconium compound and the like. Alternatively, in step “g” acompound of formula 16 is transformed in an organometal derivative, suchas a boron-pyrazolo derivative, which in turn in step“h” iscross-coupled to a suitable electrophile, such as an aryl halidecompound of formula 20, to form a compound of formula 18. In step “i” acompound of formula 18 is then deprotected to give a compound of formula(II)A. Finally, in step “j” the introduction of the —(CH₂)_(m)R1 groupto form a compound of formula (II) is accomplished through N-alkylationof a suitable alkylating agent L-(CH₂)_(m)R1. The latter reaction couldyield a mixture of regioisomers from which the desired isomer ispurified by known methods such as silica gel chromatography orpreparative HPLC.

According to step “a” of method B, a compound of formula 11 is reactedwith the Vilsmeier reagent, which can be prepared according to methodswell known by those skilled in the art, following conditions such asthose reported by Arnold (Arnold, Z. Coll. Czech. Chem. Commun., 1963,28, 863). Condensation of the malonaldehyde derivative withhydroxylamine is accomplished using solvent such as ethanol,tetrahydrofuran or the like at a temperature ranging from 0° C. toreflux and for a time ranging from 30 minutes to about 24 hours.

According to step “b” of method B, ring-opening of the isoxazole offormula 12 is accomplished using aqueous alkali, such as NaOH, KOH, LiOHor the like, optionally in the presence of a suitable solvent such asethanol, methanol, tetrahydrofuran or the like.

According to step “c” of method B, the conversion of a compound offormula 13 into a compound of formula 14 is accomplished by usinghydrazine in a suitable solvent such as tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, methanol, ethanol, acetonitrile, acetic acid,N,N-dimethylformamide or mixtures thereof at a temperature ranging from0° C. to reflux and for a time ranging from 30 minutes to about 24hours.

According to step “d” of method B, the conversion of a compound offormula 14 into a compound of formula 15 is accomplished preparing adiazonium salt, which can be done using sodium nitrite in water oraqueous solvents, in the presence of a mineral acid, such ashydrochloric acid, sulphuric acid and the like, following treatment witha iodide salt such as KI, NaI, CsI, CuI optionally in the presence ofiodine. Alternatively the diazonium salt can be obtained using isoamylnitrite in a suitable solvent such as dichloromethane dimethoxyethane,tetrahydrofuran and the like at a temperature ranging from 0° C. toreflux and for a time ranging from 30 minutes to about 24 hours.

According to step “e” of method B, protection of a iodopyrazolederivative of formula 15 can be accomplished in a number of ways whichare well-known to those skilled in the art, depending on the nature ofsuch a protecting groups. For instance protection can be carried outusing p-methoxybenzyl bromide in solvents such as N,N-dimethylformamidein the presence of a suitable base such as Cs₂CO₃, K₂CO₃ or the like attemperature ranging from 20° C. to reflux and for a time ranging from 30minutes to about 24 hours. As an alternative the protection may beaccomplished using dihydropyrane in solvents such as dichloromethane,tetrahydrofuran or the like, in the presence of a suitable catalyst suchas, for instance, p-toluenesulfonic acid (PTSA) at temperature rangingfrom 20° C. to reflux and for a time ranging from 30 minutes to about 24hours. Yet, in a further context, said protection may be accomplishedusing trityl chloride in solvents such as toluene dichloromethane,tetrahydrofuran or the like in the presence of a base such as triethylamine, DBU, or the like. Again, when such a protective group isrepresented by a SEM or SES group, protection can be accomplished usinga suitable silylating agent, such as SEM halide or SES halide in thepresence of a base, such as, for instance,1,8-diazabicyclo[5.4.0]undec-7ene (DBU). Such reactions can be performedusing a variety of solvents such as dichloromethane, toluene,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, acetonitrile at atemperature ranging from 0° C. to reflux and for a time ranging from 30minutes to about 24 hours.

According to step “f” of method B, an intermediate of formula 16 iscross-coupled with a suitable organometal, such as, for instance, anorganoboron compound (Suzuki reaction), an organotin compound (Stillereaction), an organozinc, organoalluminium or organozirconium compound(Negishi reaction), and the like. Said reactions are well known amongthose with ordinary skills in the art. Preferred reaction is the Suzukireaction where an appropriate aryl or heteroaryl boronate is used in thepresence of a palladium-based catalyst, such as, for instance, palladiumtetrakis triphenyl phosphine, and a suitable base, such as Cs₂CO₃,K₂CO₃, Rb₂CO₃, NaOH, CsF, and the like.

According to step “g” of method B, a compound of formula 18 can beobtained also by transforming a compound of formula 16 into a suitableorganometal derivative, such as an organoboron, an organotin or thelike. Preferred organometal are organoboron compounds that can beobtained for instance reacting a compound of formula 16 with a suitableboron compound, such as bis(pinacolato)diboron, pinacolborane, or thelike in the presence of a suitable palladium catalyst such as palladiumacetate, PdCl2(dppf) and of a suitable base, such as KOAc, triethylamineand the like, in solvents such as N,N-dimethylformamide,dimethylsulfoxide, dimethoxyethane, dioxane, tetrahydrofuran or thelike, at temperature ranging from 20° C. to reflux and for a timeranging from 30 minutes to about 24 hours.

According to step “h” of method B, the organometal derivative is reactedwith an appropriate electrophile of formula 20, such as an aryl halideor a trifluoromethanesulfonate (triflate), a methanesulfonate (mesylate)or a p-toluenesulfonate (tosylate) in the presence of a palladium ornickel-based catalyst, such as, for instance, palladium tetrakistriphenyl phosphine, and a suitable base, such as Cs₂CO₃, K₂CO₃, Rb₂CO₃,NaOH, CsF, and the like to give a compound of formula 18.

According to step “i” of methods B, the removal of the protecting groupPG₂ can be accomplished in a number of ways depending on the nature ofsaid protecting group. For instance, when PG₂ is a tetrahydropyranylgroup, transformation of a compound of formula 18 to a compound offormula (II)A can be accomplished using hydrochloric acid in methanol orethanol. When said protecting group is, for instance, p-methoxybenzyl ortrityl, transformation of a compound of formula 18 into a compound offormula (II)A can be accomplished using strong acids such as forinstance trifluoroacetic acid in a suitable cosolvent such asdichloromethane at temperature ranging from 20° C. to reflux or above,provided that the reaction is carried out in a sealed vial heating forinstance with a microwave oven, for a time ranging from 30 minutes toabout 24 hours.

According to step “j” of method B, the conversion of a compounds offormula (II)A into another compound of formula (II) is accomplished asdescribed under step “h” of method A.

Method C

In the above scheme, X, m, R1, R2, R3, R4, R5, R6, G, L and M are asdefined above, Hal is halogen and PG₃ is an ortho-directing protectinggroup such as tetrahydropyranyl, trimethylsilylethoxymethyl (SEM),methoxyethoxymethyl (MEM) or benzyloxymethyl (BOM).

In a further synthetic process for the preparation of a compound offormula (II), which is described in method C, in step “a” an aromaticketone of formula 10 is condensed with N,N-dimethylformamide dialkylacetal to form an enaminone derivative of formula 22, which in steps “b”and “e” is condensed with an appropriate hydrazine to form a pyrazolecompound. With a substituted hydrazine the latter reaction may yield amixture of regioisomers from which the compound of formula 24 can beseparated and purified by silica gel chromatography or preparative HPLC.When hydrazine is used (m is O and R1 is hydrogen), an N-unsubstitutedpyrazole of formula 23 is obtained. In the latter case in step “g” theintroduction of the —(CH₂)_(m)R1 group to form a compound of formula 24is accomplished through N-alkylation with a suitable alkylating agent offormula L-(CH₂)_(m)R1. In steps “c” and “f” pyrazoles of formula 23 and24 are then respectively transformed into halogenated compounds offormula 25 and 26 respectively by reaction with a N-halosuccinimide, forinstance, N-iodosuccinimide.

Alternatively, a compound of general formula 25 can be obtained startingfrom an organometal reagent of formula 21, such as a boron-pyrazoloderivative, which, in step “q”, is cross-coupled with a suitableelectrophile, such as an heteroaryl halide of formula 35, to form acompound of formula 36, which in step “r” is halogenated to form acompound of formula 37. The latter in step “s” is deprotected to give acompound of general formula 25. In step “d” a compound of formula 25 istransformed into a compound of formula 26 through N-alkylation with asuitable alkylating agent of formula L-(CH₂)_(m)R1 analogously to step“g”.

A compound of formula 26 makes up a key intermediate that can betransformed into a compound of formula (II) following a number ofsynthetic routes.

For instance, in step “h” a compound of formula 26 is transformeddirectly into a compound of formula (II) by exploiting any of thecross-coupling reactions suitable for the formation of carbon-carbonbonds. Said reactions, which are well known in the art, imply couplingwith a suitable organometal reagent, such as, for instance, anorganoboron compound (Suzuki reaction).

Alternatively, in step “o” a compound of formula 26 is transformed in anorganometal derivative, such as a boron-pyrazolo derivative which instep “p” is cross-coupled to a suitable electrophile, such as anheteroaryl halide of formula 29, to form a compound of formula (II).

Alternatively, in step “k” a compound of formula 26 is cross-coupledwith a suitable enol ether to give a compound of formula 32 by atwo-step sequence involving cross-coupling with a suitable enol etherorganometal derivative followed by hydrolysis of the enol etherintermediate.

Alternatively, in step “i” a compound of formula 26 is subjected to aSonogashira type reaction with trimethylsilylacetylene to form anintermediate of formula 30. In step “j” desilylation of the latterfollowing hydration of the intermediate alkyne that is carried out instep “I”, yields a compound of formula 32. In step “m” thetransformation of a compound of formula 32 into a compound of formula(II) is accomplished by forming the enaminone derivative of formula 33,which, in step “n” is condensed with an appropriate guanidine derivativeor an S-alkyl isothiourea derivative to give a compound of formula (II)wherein X is a Nitrogen atom.

According to step “a” of method C, synthesis of the enaminone derivativeof formula 22 is accomplished as described for step “f” of method A.

According to step “e” of method C, the conversion of the compound offormula 22 into the compound of formula 24 is accomplished as describedunder step “g” of method A.

According to step “b” of method C, wherein hydrazine is used (m is O andR1 is hydrogen), an N-unsubstituted pyrazole of formula 23 is obtained.The reaction is conducted as described under step“g1” of method A.

According to steps “d” and “g” of method C, conversion of a compound offormula 23 or 25 in another compound of formula 24 or 26 respectively isaccomplished as described under step “h” of method A.

According to steps “c” and “f” of method C, transformation of a compoundof formula 23 or 24 in a compound of formula 25 or 26 respectively canbe accomplished using a number of halogenating agents. Preferred is theiodination, which can be accomplished using iodine, iodine monochloride,or N-Iodo succinimide. Reaction with iodine is carried out for instanceusing solvents such as acetonitrile, toluene dichloromethane or waterand the like, optionally in the presence of KI or of a base such astriethylamine, K₂CO₃, NaOH and the like, at temperatures ranging from−20° C. to reflux and for a time ranging from 30 minutes to about 48hours. Reaction with iodine monochloride is carried out using solventssuch as acetic acid, dichloromethane or the like at temperatures rangingfrom −20° C. to reflux and for a time ranging from 30 minutes to about48 hours. Preferably said reaction is carried out using N-Iodosuccinimide in solvents such as N,N-dimethylformamide orN,N-dimethylacetamide at temperatures ranging from −20° C. to reflux andfor a time ranging from 30 minutes to about 48 hours.

According to step “q” of method C, an organometal reagent of formula 21is coupled with a suitable electrophile as described under step “h” ofMethod B.

According to step “r” of method C, a protected arylpyrazole of formula36 is transformed into an halogenated derivative of formula 37 asdescribed for steps “c” and “f” of method C.

According to step “s” of method C, the removal of the protecting groupPG₃ can be accomplished in a number of ways depending on the nature ofsaid protecting group. For instance, when PG₃ is a tetrahydropyranylgroup, a trimethylsilylethoxymethyl group (SEM) or a methoxyethoxymethyl(MEM) a transformation of a compound of formula 37 to a compound offormula 25 can be accomplished using hydrochloric acid in methanol orethanol. When PG₃ is a benzyloxymethyl group, deprotection can also beachieved by catalytic hydrogenation.

According to step “h” of method C, the intermediate of formula 26 can becross-coupled with a suitable oragnometal, such as, for instance, anorganoboron compound (Suzuki reaction), an organotin compound (Stillereaction), an organozinc, organoalluminium or organozirconium compound(Negishi reaction), and the like. Said reactions well known among thosewith ordinary skills in the art are accomplished as described under step“f” of method B.

According to step “o” of method C, a compound of formula (II) canalternatively be obtained by transforming a compound of formula 26 intoa suitable organometal derivative, such as an organoboron, an organotinor the like as described under step “g” of method B.

According to step “p” of method C, said organometal derivative isreacted with an appropriate electrophile as described under step “h” ofmethod B.

According to step “k” of method C, a compound of formula 26 iscross-coupled with a suitable enol ether organometal derivative, such as1-ethoxyvinyltri-n-butyltin following hydrolysis of the enol etherintermediate.

According to step “i” of method C, a compound of formula 26 is reactedwith trimethylsilylacetylene in the presence of a suitable palladiumcatalyst such as PdCl2(PPh₃)₂, Pd(PPh₃)₄, and the like, and of asuitable copper catalyst, such as CuI. Said reaction is carried out inthe presence of a suitable base, such as triethylamine, diethylamine,diisopropylamine and the like, optionally in the presence of a phosphineligand, such as triphenylphosphine. The reaction is normally carried outat temperatures ranging from −20° C. to reflux and for a time rangingfrom 30 minutes to about 48 hours.

According to step “j” of method C, the trimethylsilyl group is removedusing a base such as KOH, NaOH, K₂CO₃, in a solvent such as methanol,ethanol or the like or using a suitable fluoride salt, such as KF,n-Bu₄NF in solvents such as tetrahydrofuran, dimethoxyethane,N,N-dimethylformamide or the like.

According to step “l” of method C, the hydration of the alkyne offormula 31 to give a compound of formula 32 is accomplished using, forinstance acetic acid, trifluoroacetic acid, trifluoromethansulfonicacid, Hg(OTf)₂, NaHSO₃, and the like in a suitable aqueous solvent suchas acetonitrile, dioxane, ethanol or the like.

According to step “m” of method C, the synthesis of the enaminonederivative of formula 33 is accomplished as described under step “f” ofmethod A.

According to step “n” of method C, the condensation of the compound offormula 33 with a compound of formula 34 to form a compound of formula(II) is accomplished using solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, water, tetrahydrofuran, dioxane, dimethoxyethane,acetonitrile, ethanol, isopropanol or mixture thereof, optionally in thepresence of a suitable base such as sodium ethoxide, sodium methoxide,K₂CO₃, NaOH, DBU, or the like at temperatures ranging from 20° C. toreflux and for a time ranging from 30 minutes to about 48 hours.

Method D

In the above scheme, m, R1, R2, R3, R4, R5, R6, G, L and Hal are asdefined above.

In a further synthetic process for the preparation of a compound offormula (II), which is described in method D, in step “a” a suitableheteroaryl halide of formula 29 is subjected to a Sonogashira reactionin the presence of a suitable aryl alkyne of formula 38 to form acompound of formula 39. In step “b” the latter compound is reacted witha diazoalkane derivative, such as trimethylsilyl diazomethane, to form acompound of formula (II)A. In step “c” the introduction of the—(CH₂)_(m)R1 group to form a compound of formula (II) is accomplishedthrough N-alkylation of the suitable alkylating agent of formulaL-(CH₂)_(m)R1. The latter reaction could yield a mixture of regioisomersfrom which the desired isomer is purified by known methods such assilica gel chromatography or preparative HPLC.

According to step “a” of method D, a compound of formula 29 is coupledto an alkyne of formula 38 by means of a Sonogashira reaction, in thepresence of a suitable palladium catalyst such as PdCl2(PPh₃)₂,Pd(PPh₃)₄, and the like, and of a suitable copper catalyst, such as CuI.Said reaction is carried out in the presence of a suitable base, such astriethylamine, diethylamine, diisopropylethylamine and the like,optionally in the presence of a phosphine ligand, such astriphenylphosphine. The reaction is normally carried out at temperaturesranging from −20° C. to reflux and for a time ranging from 30 minutes toabout 48 hours.

According to step “b” of method D, the reaction of a compound of formula39 with trimethylsilyl diazomethane is carried out in solvents such asdichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, tolueneor the like at temperatures ranging from −20° C. to reflux and for atime ranging from 30 minutes to about 48 hours. Aqueous work up,optionally in the presence of an acid such as for instance hydrochloricacid, yields a compound of formula (II)A.

According to step “c” of method D, a compound of formula (II)A isconverted into another compound of formula (II) by reaction with acompound of formula L-(CH₂)_(m)R1, as described under step “h” of methodA.

A compounds of formula (II) prepared according to method A, method B,method C and method D may be further transformed in another compound offormula (II) following procedures well known to those skilled in theart. For instance, a compound of formula (II)B, i.e. a compound offormula (II) wherein X is CH group and R2 is hydrogen, or a compound offormula (II)K, i.e. a compound of formula (II) wherein X is CH group andR2 is halogen, said compound can further be transformed in anothercompound of formula (II)C, (II)D, (II)E and (II)F wherein R2 isrespectively NR14R15, NHR14, NH₂ or NHCOR16, according to method Edescribed below.

Method E

In the above scheme, m, R1, R3, R4, R5, R6, G, R14, R15, R16 and Hal areas defined above.

In a synthetic process for the preparation of a compound of formula(II)C, (II)D, (II)E and (II)F which is described in method E, in step“a” the pyridine nitrogen of a compound of formula (II)B is oxidized toform a N-oxide derivative of formula 40. In step “b”, and “c”respectively, the reaction of the latter with a suitable electrophilicspecies such as tosyl anhydride in the presence or followed by treatmentwith a suitable nucleophile such as a secondary (NHR14R15) or a primary(NH₂R14) amine yields a compound of formula (II)C and (II)Drespectively. Alternatively, in step “b1” and “c1” respectively, acompound of formula (II)K is reacted with a suitable nucleophile such asa secondary (NHR14R15) or a primary (NH₂R14) amine to yield a compoundof formula (II)C and (II)D respectively. Optionally in step “d”, whenR14 is represented by a t-Butyl group, a benzyl group or the like, saidgroups may be removed for instance by treatment with acid or underreductive conditions to yield a compound of formula (II)E. In step “e”the latter may optionally be acylated using a suitable electrophile suchas an acyl halide to form a compound of formula (II)F.

According to step “a” of method E, the oxidation of the pyridinenitrogen is carried out using oxidizing agents well-known to thoseskilled in the art, such as, for instance, hydrogen peroxide in asolvent such as acetic acid or m-chloroperbenzoic acid in solvents suchas dichloromethane, acetone, tetrahydrofuran or the like at temperaturesranging from 0° C. to reflux and for a time ranging from 30 minutes toabout 48 hours.

According to step “b” and “c” of method E, the transformation of acompound of formula 40 into a compound of formula (II)C and (II)D isaccomplished by activating the pyridine N-oxide and reacting it with asecondary or primary amine. Activation is normally carried using asuitable electrophilic reagent, such as oxalyl chloride,trifluoromethanesulfonyl chloride, tosyl chloride, phosphoryl chloride(POCl₃), benzoyl chloride, acetic anhydride, tosyl anhydride and thelike, in a solvent such as dichloromethane, tetrahydrofuran,acetonitrile, toluene, trifluoromethyl benzene and the like. Preferredis the use of tosyl anhydride in trifluoromethyl benzene. The reactionis normally carried out in the presence of the secondary or primaryamine, and may be carried out at temperatures ranging from 20° C. toreflux and for a time ranging from 30 minutes to about 48 hours.

According to steps “b1” and “c1” of method E, the transformation of acompound of formula (II)K into a compound of formula (II)C and (II)D isaccomplished by reacting it with a secondary or primary amine insolvents such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, dimethylsulfoxide, dichloromethane, tetrandrofuran,dioxane, ethanol and the like, optionally in the presence of a suitablebase such as, for instance, K₂CO₃, NaOH, triethylamine at temperaturesranging from 20° C. to reflux and for a time ranging from 30 minutes toabout 48 hours.

According to step “d” of method E, when a primary amine such ast-butylamine or benzylamine has been used in step b, the alkylic residueof such amine may be removed. The reaction, is normally carried outusing strong acids, such as trifluoroacetic acid, optionally in thepresence of suitable co-solvent, such as dichloromethane, attemperatures ranging from 20° C. to reflux and for a time ranging from30 minutes to about 48 hours. Alternatively, said reaction is carriedout using reductive conditions, such H₂ in the presence of a suitablehydrogenation catalyst. The hydrogenation catalyst is usually a metal,most often palladium, which can be used as such or supported on carbon,in a suitable solvent such as, for instance, tetrahydrofuran,1,4-dioxane, N,N-dimethylformamide, methanol, ethyl acetate, or amixture thereof.

According to step “e” of method E, compounds of formula (II)E areconverted in a carboxamide of formula (II)F. It is clear to the skilledperson that this reaction can be accomplished in a variety of ways andoperative conditions, which are widely known in the art for thepreparation of carboxamides. As an example, a compound of formula (II)Eis acylated with a compound of formula R16COHal, wherein Hal is anhalogen, such as chloride; the reaction is performed in a suitablesolvent such as, for instance, dichloromethane, chloroform,tetrahydrofuran, diethyl ether, 1,4-dioxane, acetonitrile, toluene, orN,N-dimethylformamide, in the presence of a suitable base such astriethylamine, diisopropyl ethylamine, DBU and the like at a temperatureranging from about −10° C. to reflux and for a suitable time, forinstance from about 30 minutes to about 96 hours.

A compound of formula (II) prepared according to method A, method B,method C and method D may be further transformed in another compound offormula (II) following procedures well known to those skilled in theart. For instance, a compound of formula (II)G, i.e. a compound offormula (II) wherein X is nitrogen and R2 is thiomethyl, or a compoundof formula (II)L, i.e. a compound of formula (II) wherein X is nitrogenand R2 is halogen, said compound can further be transformed in othercompounds of formula (II)H, (11)1 and (II)J wherein R2 is respectivelyNR14R15, NH₂ or NHCOR16, according to method F described below.

Method F

In the above scheme, m, R1, R3, R4, R5, R6, G, R14, R15, R16 and Hal areas defined above.

In a synthetic process for the preparation of a compound of formula(II)H, (II)I and (II)J which is described in method F, in step “a” thereaction of a compound of formula (II)G with an oxidizing agent yields asulfonyl derivative of formula 41. In step “b” the latter is treatedwith a suitable nucleophile such as a primary or secondary amine offormula NHR14R15 to give a compound of formula (II)H. In step “c” thesulfonyl derivative of formula 41 is treated with ammonium chloride toform a compound of formula (II)1. Alternatively, in step “b1” and “c1”,a compound of formula (II)L is reacted with a suitable nucleophile suchas a primary or secondary amine of formula (NHR14R15) or with ammoniumchloride to yield a compound of formula (II)H and (II)I respectively. Acompound of formula (II)I may optionally be acylated using a suitableelectrophile of formula R16COHal, wherein Hal is an halide, such aschloride or the like to form a compound of formula (II)J.

According to step “a” of method F, the oxidation of the thiomethyl groupis carried out using oxidizing agents well-known to those skilled in theart, such as, for instance, oxone in a suitable solvent such astetrahydrofuran, dioxane, acetone, optionally in the presence of wateras a cosolvent, or m-chloroperbenzoic acid in solvents such asdichloromethane, acetone, tetrahydrofuran or the like at temperaturesranging from 0° C. to reflux and for a time ranging from 30 minutes toabout 48 hours.

According to step “b” and “b1” of method F, the transformation of acompound of formula 41 in a compound of formula (II)H is carried outusing a primary or secondary amine of formula R14R15NH in solvents suchas N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,dimethylsulfoxide, dichloromethane, tetrandrofuran, dioxane, ethanol andthe like, optionally in the presence of a suitable base such as, forinstance, K₂CO₃, NaOH, triethylamine at temperatures ranging from 20° C.to reflux and for a time ranging from 30 minutes to about 48 hours.

According to step “c” and “c1” of method F, the formation of a compound(II)I from a compound of formula 41 is accomplished using a solution ofammonia in a suitable solvent, such as, dichloromethane, ethanol and thelike, or ammonium salts, such as, for instance ammonium acetate insolvents such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, dimethylsulfoxide and the like at temperaturesranging from 20° C. to reflux and for a time ranging from 30 minutes toabout 48 hours.

According to step “d” of method F, a compound of formula (II)1 may beconverted in a carboxamide of formula (II)J. It is clear to the skilledperson that this reaction can be accomplished in a variety of ways andoperative conditions, which are widely known in the art for thepreparation of carboxamides. As an example, a compound of formula (II)1is acylated with a compound of formula R16COHal, wherein Hal is anhalogen, such as chloride; the reaction is performed as described understep “e” of method E.

The compound of formula (I) can be prepared according to any of themethods G, H, I, J and M described below, provided that the interferingamino groups are protected by the introduction of suitable protectinggroups, as can be understood by those skilled in the art.

According to method G described below, starting from a compound offormula (II)1, i.e. a compound of formula (II) wherein G is nitro, orfrom a compound of formula (II)2, i.e. a compound of formula (II)wherein G is a protected amino group, a compound of formula (I)C, (I)D,(I)E (I)F, (I)G or (I)H wherein A is respectively NHSO₂, NHCOO,NHCON(Y), NHCSNH, NHCO or SO₂N(Y) is prepared.

Method G

In the above scheme, X, m, R1, R2, R3, R4, R5, R6, R7 and Y are asdefined above, R7′ is as R7 described above but not hydrogen and W is asuitable leaving group such as hydroxy or halogen, and PG₄ is a suitableprotecting group of the amino moiety such as benzyl, bis-benzyl,p-methoxybenzyl, trityl, phtaloyl, benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, and the like.

In a synthetic process for the preparation of a compound of formula from(I)C to (I)H which is described in method G, in step “a” a compound offormula (II)1 is converted into a compound of formula 42 by reducing thenitro group to amino group. In step “b”, said compound of formula 42 isobtained by removal of a suitable protecting group of the amino moietyfrom a compound of formula II(2).

In step “c”, “d”, “e”, “g” and h″ said compound of formula 42 is thenreacted with different types of electrophile to provide respectively acompound of formula (I)C, (I)D, (I)E, (I)F and (I)G. In step “f”, acompound of formula (I)D is converted into a compound of formula (I)E byreaction with a suitable primary or secondary amine. In step “i” acompound of formula 42 is subjected to a diazotation reaction under theSandmeier conditions following reaction with SO₂ in the presence ofhydrochloric acid and a suitable copper catalyst to form a sulfonylchloride of formula 44. In step “j” the latter compound is reacted witha suitable primary amine to yield a compound of formula (I)H.

According to step “a” of method G, the nitro group of a compound offormula (II)1 is reduced to amino group to yield a compound of formula42. The reaction may be carried out in a variety of way and operativeconditions, which are widely known in the art for reducing a nitro to anamino group. Preferably, this reaction is carried out in a suitablesolvent such as, for instance, water, methanol, tetrahydrofuran,1,4-dioxane, N,N-dimethylformamide, ethyl acetate, or a mixture thereof,in the presence of a suitable reducing agent, such as, for instance,hydrogen and a hydrogenation catalyst, or by treatment with cyclohexeneor cyclohexadiene and a hydrogenation catalyst, or by treatment with tin(II) chloride, or by treatment with zinc or zinc (II) chloride andaqueous hydrochloric acid or acetic acid or ammonium chloride, at atemperature ranging from 0° C. to reflux and for a time varying fromabout 1 hour to about 96 hours. The hydrogenation catalyst is usually ametal, most often palladium, which can be used as such or supported oncarbon.

According to step “b” of method G, when the PG₄ is a protecting groupsuch as benzyl (NHCH₂Ph), bisbenzyl (N(CH₂Ph)₂), p-methoxybenzyl,p-methoxyphenyl, trityl, benzyloxycarbonyl, or p-nitrobenzyloxycarbonylgroup, deprotection can be accomplished using H₂ in the presence of asuitable hydrogenation catalyst. The hydrogenation catalyst is usually ametal, most often palladium, or a metal derivative, such as Pd(OH)₂,which can be used as such or supported on carbon, in a suitable solventsuch as, for instance, tetrahydrofuran, 1,4-dioxane,N,N-dimethylformamide, methanol, ethyl acetate, or a mixture thereof.Alternatively, said deprotection can be accomplished using strong acids,such as, for instance, sulphuric acid, hydrochloric acid,trifluoroacetic acid, trifluoromethanesulfonic acid or the like in thepresence of a suitable solvent such as toluene, acetonitrile,dichloromethane or the like at a temperature ranging from 0° C. toreflux and for a time varying from about 1 hour to about 96 hours. Inaddition, when such a protecting group is a p-methoxyphenyl group,deprotection can be accomplished also under oxidative conditions, usingfor instance cerium ammonium nitrate (CAN) in a suitable solvent such asacetonitrile, dioxane, water methylethylketone or mixture thereof, at atemperature ranging from 0° C. to reflux and for a time varying fromabout 1 hour to about 24 hours. When said protecting group isrepresented by a phtaloyl group removal of the protecting group can beaccomplished using hydrazine in a suitable solvent such as ethanol,water, dioxane, tetrahydrofuran and the like at a temperature rangingfrom 0° C. to reflux and for a time varying from about 1 hour to about96 hours.

According to step “c” of method G, a compound of formula 42 is reactedwith a sulfonyl chloride in the presence of a suitable base, such as forinstance, pyridine, N-methyl morpholine, diisopropyl ethylamine, in theappropriate solvent such as pyridine, dichloromethane ortetrahydrofuran, at a temperature ranging from 0° C. to reflux and for atime varying from about 1 hour to about 7 days.

According to step “d” of method G, a compound of formula 42 ispreferably reacted with a chloroformate in the appropriate solvent suchas tetrahydrofuran, N,N-dimethylformamide, dichloromethane, chloroform,acetonitrile, toluene or mixtures thereof, at a temperature ranging fromabout −10° C. to reflux and for a time varying from about 30 minutes toabout 96 hours. The reaction is normally carried out in the presence ofan opportune proton scavenger such as triethylamine,N,N-diisopropylethylamine or pyridine.

According to step “e” of method G, a compound of formula 42 is reactedwith the appropriate isocyanate in a suitable solvent such as adichloromethane or tetrahydrofuran to yield an urea of formula (I)E. Thereaction is normally carried out at a temperature ranging from about−10° C. to reflux and for a time varying from about 30 minutes to about96 hours.

According to step “f” of method G, a compound of formula (I)E isobtained also from a compound of formula (I)D by reaction with anappropriate amine of formula R7N(Y)H. Said reaction is typically carriedout in the appropriate solvent such as dimethylsulfoxide,tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide,acetonitrile, toluene or mixtures thereof, optionally in the presence ofa further base such as TEA, DIPEA DBU or an organometallic reagent suchas a Grignard reagent or trimethyl aluminium, at a temperature rangingfrom about −10° C. to reflux and for a time varying from about 30minutes to about 96 hours.

According to step “g” of method G, a compound of formula 42 is reactedwith an appropriate thioisocyanate in a suitable solvent such asdichloromethane or tetrahydrofuran to yield a thiourea of formula (I)F.The reaction is normally carried out at a temperature ranging from about−10° C. to reflux and for a time varying from about 30 minutes to about96 hours.

According to step “h” of method G, a compound of formula 42 istransformed into an amide of formula (I)G by condensation with anyderivative of formula 43. It is clear to the skilled person that thisreaction can be accomplished in a variety of ways and operativeconditions, which are widely known in the art for the preparation ofcarboxamides.

As an example, when W is an halogen such as chloride, the reaction isperformed in a suitable solvent such as, for instance, dichloromethane,chloroform, tetrahydrofuran, diethyl ether, 1,4-dioxane, acetonitrile,toluene, or N,N-dimethylformamide or the like at a temperature rangingfrom about −10° C. to reflux and for a suitable time, for instance fromabout 30 minutes to about 96 hours. The reaction is carried out in thepresence of an opportune proton scavenger such as triethylamine,N,N-diisopropylethylamine or pyridine. When W is an hydroxy group, thereaction is carried out in the presence of a coupling agent such as, forinstance, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TBTU), 1,3-dicyclohexylcarbodiimide,1,3-diisopropylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,N-cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene orN-cyclohexylcarbodiimide-N′-methyl polystyrene, in a suitable solventsuch as, for instance, dichloromethane, chloroform, tetrahydrofuran,diethyl ether, 1,4-dioxane, acetonitrile, toluene, orN,N-dimethylformamide at a temperature ranging from about −10° C. toreflux and for a suitable time, for instance from about 30 minutes toabout 96 hours. The said reaction is optionally carried out in thepresence of a suitable catalyst, for instance 4-dimethylaminopyridine,or in the presence of a further coupling reagent such asN-hydroxybenzotriazole. Alternatively, this same reaction is alsocarried out, for example, through a mixed anhydride method, by using analkyl chloroformate such as ethyl, iso-butyl, or iso-propylchloroformate, in the presence of a tertiary base such as triethylamine,N,N-diisopropylethylamine or pyridine, in a suitable solvent such as,for instance, toluene, dichloromethane, chloroform, tetrahydrofuran,acetonitrile, diethyl ether, 1,4-dioxane, or N,N-dimethylformamide, at atemperature ranging from about −30° C. to room temperature.

According to step “i” of method G, the amino group of a compound offormula 42 is subjected to a diazotation reaction under the Sandmeierconditions following reaction with SO₂ in the presence of hydrochloricacid and a suitable copper catalyst to form a sulfonyl chloride offormula 44. The diazotation reaction is performed using sodium nitritein water or aqueous solvents, in the presence of a mineral acid, such ashydrochloric acid, sulphuric acid and the like, or using isoamyl nitritein a suitable solvent such as dichloromethane, dimethoxyethane,tetrahydrofuran and the like at a temperature ranging from 0° C. toreflux and for a time ranging from 30 minutes to about 24 hours. Nextthe diazonium salt is typically reacted with SO₂ in the presence ofCuCl2 in the suitable solvent such as water, acetic acid or mixturesthereof at a temperature ranging from 0° C. to about 50° C. and for atime ranging from 30 minutes to about 6 hours.

According to step “j” of method G, a compound of formula 44 is reactedwith a suitable amine to yield a compound of formula (I)H. Said reactionis normally carried out in a suitable solvent such as, for instance,dichloromethane, chloroform, tetrahydrofuran, diethyl ether,1,4-dioxane, acetonitrile, toluene, or N,N-dimethylformamide or the likeat a temperature ranging from about −10° C. to reflux and for a suitabletime, for instance from about 30 minutes to about 96 hours. The reactionmay be carried out in the presence of an opportune proton scavenger suchas triethylamine, N,N-diisopropylethylamine or pyridine.

According to method H described below, starting from a compound offormula (II)3, i.e. a compound of formula (II) wherein G is bromine, acompound of formula (I)1 or (I)J wherein A is respectively CH₂SO₂N(Y) orCH₂CON(Y) is prepared.

Method H

In the above scheme, X, m, R1, R2, R3, R4, R5, R6, E, R7, Alk, and Y areas defined above.

In a synthetic process for the preparation of a compound of formula (I)Iand (I)J which is described in method H, in step “a” a compound offormula (II)3 is transformed in a compound of formula 45 by reactionwith a suitable methanesulfonamide or alkylsulfonylamidoacetate offormula 49, in the presence of a suitable base, palladium-based catalystand ligand. In step “b” the latter compound is than reacted with asuitable amine to form a compound of formula (I)I.

In step “c” a compound of formula (II)3 is reacted with an alkylmalonate salt in the presence of a suitable copper catalyst to form acompound of formula 46 which in step “d” is then hydrolyzed to thecorresponding carboxylic acid of formula 47 by means of any of methodsknown in the art, for instance by using lithium hydroxide in thepresence of suitable solvents such as mixtures of tetrahydrofuran,methanol and water. Said compound of formula 47 in step “e” is thencondensed with a suitable amine to form a compound of formula (I)J.Alternatively, a compound of formula (II)3 is aminated under theBuchwald-Hartwig reaction conditions using benzophenone imine, asuitable base and a palladium catalyst to form a compound of formula 48.In step “g” the latter is hydrolyzed under acidic conditions, forinstance using hydrochloric acid to form a compound of formula 42 thatis subjected to any of the reactions reported in method G shown above.

According to step “a” of method H, the reaction between a compound offormula (II)3 and a suitable methylsulfonamide or alkylsulfonylamidoacetate such as 4-methanesulfonyl-morpholine of formula 49, is carriedout following the conditions reported by Gimm, J. B.; Katcher, M. H.;Witter, D. J.; Northrup, A. B.; (J. Org. Chem. 2007, 72 (21),8135-8138), using a base such as, for instance, sodium tertbutoxide, asuitable palladium catalyst, such as Pd(OAc)₂, a ligand, such astriphenylphosphine or tri tertbutylphosphonium tetrafluoroborate. Saidreaction is normally carried out in solvents such as dioxane,dimethoxyethane and the like at a temperature ranging from about 0° C.to reflux and for a suitable time, for instance from about 30 minutes toabout 96 hours. In case an alkylsulfonylamido acetate is used (compounds48 where E is an alkyloxycarbonyl group) said reaction is followed bytreatment with a variety of bases, such as, for instance K₂CO₃ or sodiumamide in a suitable solvent such as 1,4-dioxane, dimethyl sulfoxideN,N-dimethylformamide or the like at a temperature ranging from about20° C. to reflux and for a suitable time, for instance from about 30minutes to about 96 hours.

According to step “b” of method H, the reaction between a compound offormula 45 and an amine is normally carried out in a suitable solvent,such as 1,4-dioxane, acetonitrile, toluene, or N,N-dimethylformamide orthe like at a temperature ranging from about 20° C. to reflux and for asuitable time, for instance from about 30 minutes to about 96 hours.

According to step “c” of method H, the reaction between a compound offormula (II)3 and a suitable alkyl acetate or alkyl malonate of formula50, is carried out using a base such as, for instance, sodium hydride, asuitable catalyst, such as CuBr, Pd(OAc)₂ or PdCl2 a ligand, such as,for instance triphenylphosphine. Said reaction is normally carried outin solvents such as dioxane, dimethoxyethane and the like at atemperature ranging from about 0° C. to reflux and for a suitable time,for instance from about 30 minutes to about 96 hours. In case an alkylmalonate is used (i.e. a compound of formula 50 where E is analkyloxycarbonyl group) said reaction is followed by treatment with abase, such as, for instance K₂CO₃ or sodium amide in a suitable solventsuch as 1,4-dioxane, dimethyl sulfoxide N,N-dimethylformamide or thelike at a temperature ranging from about 20° C. to reflux and for asuitable time, for instance from about 30 minutes to about 96 hours.

According to step “d” of method H, the hydrolysis of the alkyl ester offormula 46 is carried out according to well-known methods, for instancein the presence of aqueous alkaline solutions such as aqueous sodiumhydroxide or lithium hydroxide in solvents such as tetrahydrofuran,methanol water and mixtures thereof. Said reaction typically requiresfrom 30 minutes to 96 hours and is carried out at a temperature rangingfrom 0° C. to reflux.

According to step “e” of method H, a compound of formula 47 istransformed in an amide of formula (I)J by the condensation with asuitable amine. It is clear to the skilled person that this reaction canbe accomplished in a variety of ways and operative conditions, which arewidely known in the art for the preparation of carboxamides. As anexample, the reaction is carried out in the presence of a coupling agentsuch as, for instance,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU), 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,N-cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene orN-cyclohexylcarbodiimide-N′-methyl polystyrene, in a suitable solventsuch as, for instance, dichloromethane, chloroform, tetrahydrofuran,diethyl ether, 1,4-dioxane, acetonitrile, toluene, orN,N-dimethylformamide at a temperature ranging from about −10° C. toreflux and for a suitable time, for instance from about 30 minutes toabout 96 hours. Said reaction is optionally carried out in the presenceof a suitable catalyst, for instance 4-dimethylaminopyridine, or in thepresence of a further coupling reagent such as N-hydroxybenzotriazole.Alternatively, this same reaction is also carried out, for example,through a mixed anhydride method, by using an alkyl chloroformate suchas ethyl, iso-butyl, or iso-propyl chloroformate, in the presence of atertiary base such as triethylamine, N,N-diisopropylethylamine orpyridine, in a suitable solvent such as, for instance, toluene,dichloromethane, chloroform, tetrahydrofuran, acetonitrile, diethylether, 1,4-dioxane, or N,N-dimethylformamide, at a temperature rangingfrom about −30° C. to room temperature.

According to step “f” of method H, a compound of formula (II)3 isconverted into a compound of formula 48 by reaction with benzophenoneimine in the presence of a suitable base, such as sodium tert-buthoxide,a suitable catalyst, such as tris dibenzylidenacetone dipalladium,Pd₂(dba)₃, and optionally an additional ligand, such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), in a suitablesolvent, such as toluene, dimethoxyethane, dioxane and the like at atemperature ranging from about 20° C. to reflux and for a suitable time,for instance from about 30 minutes to about 96 hours.

According to step “g” of method H, the hydrolysis of a compound offormula 48 is accomplished using an acid such as hydrochloric acid indioxane. Said reaction is normally carried out at a temperature rangingfrom about 0° C. to 40° C. and for a suitable time, for instance fromabout 30 minutes to about 96 hours.

Further elaboration of a compound of formula 42 is carried out accordingto method G.

According to method I described below, starting from a compound offormula (II)4, i.e. a compound of formula (II) wherein G is a cyanogroup, a compound of formula (I)K, (I)L, (I)M, (I)N, (I)O or (I)Pwherein A is respectively CON(Y), CH₂NHSO₂, CH₂NHCOO, CH₂NHCONH,CH₂NHCSNH, or CH₂NHCO is prepared.

Method I

In the above scheme, X, m, R1, R2, R3, R4, R5, R6, R7, R7′, Y and W areas defined above.

In a synthetic process for the preparation of a compound of formula from(I)K to (I)P which is described in method I, in step “a” the cyano groupof a compound of formula (II)4 is hydrolized to form a compound offormula 51, and the latter in step “b” is then condensed with a suitableamine to form a compound of formula (I)K. Alternatively in step “c” thecyano group of a compound of formula (II)4 is reduced to form a compoundof formula 52. In step “d”, “e”, “f, “g” and “h” said compound offormula 52 is then reacted with different types of electrophile toprovide respectively a compound of formula (I)L, (I)M, (I)N, (I)O and(I)P.

According to step “a” of method I, the hydrolysis of the cyano group isaccomplished by using any of the method known in the art, preferably byusing aqueous hydrochloric acid under microwave heating at temperatureranging between 80 and 200° C. for a time between 3 and 120 minutes.

According to step “b” of method I, a compound of formula 51 istransformed in an amide of formula (I)K by the condensation with asuitable amine. It is clear to the skilled person that this reaction canbe accomplished in a variety of ways and operative conditions, which arewidely known in the art for the preparation of carboxamides. As anexample, the reaction is carried out in the presence of a coupling agentsuch as, for instance,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU), 1,3-dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,N-cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene orN-cyclohexylcarbodiimide-N′-methyl polystyrene, in a suitable solventsuch as, for instance, dichloromethane, chloroform, tetrahydrofuran,diethyl ether, 1,4-dioxane, acetonitrile, toluene, orN,N-dimethylformamide at a temperature ranging from about −10° C. toreflux and for a suitable time, for instance from about 30 minutes toabout 96 hours. Said reaction is optionally carried out in the presenceof a suitable catalyst, for instance 4-dimethylaminopyridine, or in thepresence of a further coupling reagent such as N-hydroxybenzotriazole.Alternatively, this same reaction is also carried out, for example,through a mixed anhydride method, by using an alkyl chloroformate suchas ethyl, iso-butyl, or iso-propyl chloroformate, in the presence of atertiary base such as triethylamine, N,N-diisopropylethylamine orpyridine, in a suitable solvent such as, for instance, toluene,dichloromethane, chloroform, tetrahydrofuran, acetonitrile, diethylether, 1,4-dioxane, or N,N-dimethylformamide, at a temperature rangingfrom about −30° C. to room temperature.

According to step “c” of method I, a compound of formula (II)4 istransformed in a compound of formula 52 by using a suitable reducingagent, for instance lithium alluminium hydride, lithium boron hydride,borane dimethylsulfide complex, borane or the like, in a suitablesolvent such as tetrahydrofuran, diethyl ether, toluene,dichloromethane, diglyme and the like, at temperature ranging from −50°to reflux, for a suitable reaction time, for instance, between 30minutes and 48 hours.

Steps from “d” to “h” of method I are respectively carried out asdescribed under step “c”, “d”, “e”, “g” and “h” of method G.

According to method J described below, starting from a compound offormula (II)5, i.e. a compound of formula (II) wherein G is G is asuitable carboxylic ester, a compound of formula (I)0 wherein A isCH₂SO₂N(Y) is prepared.

Method J

In the above scheme, X, m, R1, R2, R3, R4, R5, R6, R7, Y, Alk and L′ areas defined above.

In a synthetic process described in method J, a compound of formula 51is obtained in step “a” by the hydrolysis of the alkoxycarbonyl group ofa compound of formula (II)5. The compound of formula 51 is thensubjected to an amidation reaction according to what described in methodI, step “b”. In step “b” the alkoxycarbonyl group of compounds (II)5 isreduced to form a compound of formula 53. In step “c” the hydroxy groupof the latter is then replaced by a more suitable leaving group, forinstance bromine, a tosylate, mesylate or triflate. In step “d” acompound of formula 54 so obtained is reacted with a suitablenucleophile such as sodium sulfite, to form a compound of formula 55.Alternatively in step “g”, a compound of formula 54 is reacted withsodium azide and then, in step “h”, the intermediate alkyl azide isreduced to form a compound of formula 52 that is further functionalizedfollowing treatment with the appropriate electrophile as reported inmethod I shown above. In step “e” a compound of formula 55 is thentransformed in the corresponding chloride derivative and then in step“f” treated with a suitable amine to give a compound of formula (I)O.

According to step “a” of method J, the hydrolysis of the alkyl ester iscarried out according to well-known methods, for instance in thepresence of aqueous alkaline solutions such as aqueous sodium hydroxideor lithium hydroxide in solvents such as tetrahydrofuran, methanol waterand mixtures thereof. Said reaction typically requires from 30 minutesto 96 hours and is carried out at a temperature ranging from 0° C. toreflux.

According to step “b” of method J, the reduction of a compound offormula (II)5 is carried out by using a suitable reducing agent, forinstance lithium alluminium hydride, lithium boron hydride, borane orthe like, in a suitable solvent such as tetrahydrofuran, diethyl ether,toluene, dichloromethane and the like, at temperature ranging from −50to reflux, for a suitable reaction time, for instance, between 30minutes and 48 hours. According to step “c” of method J, the hydroxygroup of a compound of formula 53 is transformed in a more suitableleaving group following procedures well known in the art. For instance,its transformation in a bromine atom can be accomplished using anappropriate brominating agent such as Ph₃PBr₂, PBr₃, SOBr₂ or the likein a suitable solvent such as dichloromethane, tetrahydrofuran, diethylether, toluene, and the like, for a time ranging between 30 minutes to24 hours and is carried out at a temperature ranging from 0° C. toreflux. The transformation of the hydroxy group in a tosylate, mesylateor triflate group is usually carried out using suitable reagents suchas, for instance, tosyl chloride, mesyl chloride,trifluoromethanesulfonyl chloride respectively.

According to step “d” of method J, a compound of formula 54 is reactedwith reagents such as sodium sulfite in solvents such as water,N,N-dimethylformamide, acetone or mixture thereof, optionally in theadditional presence of a compound such as tetrabutyl ammonium bromide orthe like, at a temperature ranging from 20° C. to reflux and for a timeranging from 30 minutes to about 24 hours.

According to step “e” of method J, a compound of formula 54 is reactedwith reagents such as PCl₅, POCl₃, SOCl₂, (COCl)₂ or the like, in asuitable solvent such as tetrahydrofuran, dichloromethane or the like ata temperature ranging from 20° C. to reflux and for a time ranging from30 minutes to about 24 hours to form compounds of formula 56.

According to step “f” of method J, a compound of formula 56 is reactedwith a suitable amine to yield a compound of formula (I)Q. Said reactionis normally carried out in a suitable solvent such as, for instance,dichloromethane, chloroform, tetrahydrofuran, diethyl ether,1,4-dioxane, acetonitrile, toluene, or N,N-dimethylformamide or the likeat a temperature ranging from about −10° C. to reflux and for a suitabletime, for instance from about 30 minutes to about 96 hours. The reactionmay be carried out in the presence of an opportune proton scavenger suchas triethylamine, N,N-diisopropylethylamine or pyridine.

Conversion of a compound of formula 54 into a compound of formula 52 canbe accomplished in a number of ways and operative conditions wellestablished among those skilled in the art. Just as an example atwo-step sequence involving the formation of an alkyl azide of formula57 and its reduction to an amino compound of formula 52 is reportedhere.

Accordingly, in step “g” of method J, a compound of formula 54 isreacted with a compound such as sodium azide in a solvent such asN,N-dimethylformamide, acetone, tetrahydrofuran, ethanol at atemperature ranging from about 20° C. to reflux and for a suitable time,for instance from about 30 minutes to about 96 hours.

According to step “h” of method J, a compound of formula 57 is reducedto form a compound of formula 52. Said reduction is accomplished usingany suitable reducing agent such as, for instance, PPh₃, SnCl₂, BH₃ orthe like in suitable solvent such as tetrahydrofuran, ethanolN,N-dimethylformamide or the like at a temperature ranging from about20° C. to reflux and for a suitable time, for instance from about 30minutes to about 96 hours.

A compound of formula (I) prepared according to method G, method H,method I, or method J may be further converted into another compound offormula (I) following procedures well known to those skilled in the art.

For instance, a compound of formula (I)R, i.e. a compound of formula (I)wherein X is a CH group and R2 is hydrogen or a compound of formula(I)AA, i.e. a compound of formula (I) wherein X is a CH group and R2 ishalogen, said compound can further be transformed into another compoundof formula (I)S, (I)T, (I)U or (I)V wherein R2 is respectively NR14R15,NHR14, NH₂ or NHCOR16, according to method K described below.

Method K

In the above scheme, m, R1, R3, R4, R5, R6, A, R7, R14, R15, R16 and Halare as defined above.

In a synthetic process for the preparation of a compound of formula(I)S, (I)T, (I)U and (I)V which is described in method K, in step “a”the pyridine nitrogen of a compound of formula (I)R is oxidized to forma N-oxide derivative of formula 58. In step “b” and “c” respectively,the reaction of the latter with a suitable electrophilic species such astosyl anhydride in the presence or followed by treatment with a suitablenucleophile such as a secondary (NHR14R15) or a primary (NH₂R14) amineyields a compound of formula (I)S and (I)T respectively. Alternatively,in step “b1” and “c1” respectively, a compound of formula (I)AA isreacted with a suitable nucleophile such as a secondary (NHR14R15) or aprimary (NH₂R14) amine to yield a compound of formula (I)S and (I)Trespectively. Optionally in step “d”, when R14 is represented by at-butyl group, a benzyl group or the like, said groups is removed forinstance by treatment with acid or under reductive conditions to yield acompound of formula (I)U. In step “e” the latter is optionally acylatedusing a suitable electrophile such as an acyl chloride to form acompound of formula (I)V.

The reactions of steps “a”, “b”, “c”, “d”, “c1”, “d1” and “e” of methodK are accomplished analogously to those of to steps “a”, “b”, “c”, “d”,“c1”, “d1” and “e” of method E shown above.

A compound of formula (I) prepared according to method G, method H,method I, or method J may be further converted into another compound offormula (I) following procedures well known to those skilled in the art.

For instance, a compound of formula (I)W, i.e. a compound of formula (I)wherein X is nitrogen and R2 is thiomethyl or a compound of formula(I)AB, i.e. a compound of formula (I) wherein X is nitrogen and R2 ishalogen, said compound can further be transformed into another compoundof formula (I)X, (I)Y or (I)Z wherein R2 is respectively NR14R15, NH₂ orNHCOR16, according to method L described below.

Method L

In the above scheme, m, R1, R3, R4, R5, R6, A, R7, R14, R15 and R16 andHal are as defined.

In a synthetic process for the preparation of compounds of formula (I)X,(I)Y and (I)Z which is described in method L, in step “a” the reactionof a compound of formula (I)W with an oxidizing agent yields a sulfonylderivative of formula (I)W′. In step “b” the latter is treated with asuitable nucleophile such as a primary or secondary amine of formulaNHR14R15 to give a compound of formula (I)X. In step “c” the sulfonylderivative of formula (I)W′ is treated with ammonium chloride to form acompound of formula (I)Y. Alternatively, in step “b1” and “c1”, acompound of formula (I)AB is reacted with a suitable nucleophile such asa primary or secondary amine of formula (NHR14R15) or with ammoniumchloride to yield a compound of formula (I)X and (I)Y respectively. Acompound of formula (I)Y is optionally acylated using a suitableelectrophile of formula R16COHal, wherein Hal is an halide, such aschlorid or the like to form a compound of formula (I)Z.

The reactions of steps “a”, “b”, “c”, “b1”, “c1” and “d” of method L areaccomplished analogously to those of steps “a”, “b”, “c”, b1”, “c1” and“d” of method F shown above.

In a further process, a compound of formula 60 is transformed into acompound of formula (I)A, according to method M shown below.

Method M

In the above scheme, X, R2, R3, R4, R5, R6, A, R7 are as defined above,m is O, R1 is hydrogen and PG₅ is a protecting group or a resin forsolid phase synthesis.

It is readily understood by those skilled in the art, that when PG₅represents a suitable protecting group or a resin for solid phasesynthesis, a variety of methods, which are well known in the art, can beused to remove such a protecting group or resin depending on the natureof the PG₅.

According to step “a” of method M, when the PG₅ is a protecting groupsuch as a silyl group or a derivative thereof such as2-trimethylsilylethanesulfonyl (SEM), 2-trimethylsilylethanesulfonyl(SES) and the like, deprotection can be accomplished using tetrabutylammonium fluoride, cesium fluoride, as well as trifluoroacetic acid,perchloric acid, hydrochloric acid, hydrofluoric acid, and derivativesthereof, in a suitable solvent such as tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, methanol, ethanol, acetonitrile, dichloromethane,N,N-dimethylformamide or the like at a temperature ranging from 0° C. toreflux and for a time ranging from 30 minutes to about 24 hours. Whensuch a protecting group is represented by a tetrahydropyranyl group, thetransformation of a compound of formula 60 into a compound of formula(I) is accomplished using hydrochloric acid in methanol or ethanol. Whensaid protecting group is, for instance, benzyl, p-methoxybenzyl ortrityl, transformation of a compound of formula 60 into a compound offormula (I) is accomplished using strong acids such as for instancetrifluoroacetic acid in a suitable cosolvent such as dichloromethane attemperature ranging from 20° C. to reflux or above, provided that thereaction is carried out in a sealed vial heating for instance with amicrowave oven, for a time ranging from 30 minutes to about 24 hours.When said protecting group is, for instance, tert-butoxycarbonyl thetransformation of a compound of formula 60 into a compound of formula(I) is accomplished using strong acids such as for instancetrifluoroacetic acid in a suitable cosolvent such as dichloromethane orhydrochloric acid in dioxane at temperature ranging from 20° C. toreflux or above, provided that the reaction is carried out in a sealedvial heating for instance with a microwave oven, for a time ranging from30 minutes to about 24 hours. When said protecting group is, forinstance, ethoxycarbonyl the transformation of a compound of formula 60into a compound of formula (I)A is accomplished using, for instance,triethylamine in the presence of methanol or the like at temperatureranging from 20° C. to reflux for a suitable time usually between 30minutes and 48 hours.

When the PG₅ group represents a resin for solid phase synthesis, removalof such a resin is accomplished according to methods well known to thoseskilled in the art, which depend on the nature of such a resin.Typically when trityl chloride resin, 2-chlorotrityl chloride resin,4-(bromomethyl)phenoxymethyl resin, 4-(bromomethyl)phenoxyethyl resin,Bromo-(4-methoxyphenyl)methyl polystyrene resin/Bromo MAMP resin),p-nitrophenyl carbonate Wang resin, p-nitrophenyl carbonate Merrifieldresin, 3,4-dihydro-2H-pyran-2-ylmethyoxymethyl resin, p-nitrophenylcarbonate buthyloxymethyl resin, and the like are used, removal isaccomplished using trifluoroacetic acid in a suitable solvent such asdichloromethane at room temperature for a suitable time, usually between5 minutes and 24 hours.

In a further process, a compound of formula (II)A obtained by method A,method B, method C and method D is transformed into a compound offormula 61 according to method N shown below.

Method N

In the above scheme, X, R2, R3, R4, R5, R6, G and PG₅ are as definedabove.

It is readily understood by those skilled in the art, that theinstallation of PG₅ may be accomplished in a number of ways andfollowing a variety of methods, which are well known in the art,depending on the nature of the PG₅.

According to step “a′” of method N, when PG₅ is a silyl deriv,tetrahydropiranyl, p-methoxybenzyl or trityl the transformation of acompound of formula (II)A in a compound of formula 61 is accomplished asdescribed under step “e”, of method B. When PG₅ is an alkoxycarbonylgroup the transformation of a compound of formula (II)A in a compound offormula 61 is accomplished using the appropriate dialkyl carbonate, suchas for instance di-tert-butyl dicarbonate, an alkyl chlororformate, suchas for instance ethyl chloroformate, optionally in the presence of asuitable base, such as triethylamine, N,N-diisopropyl ethylamine or thelike in a suitable solvent, such as, for instance dichloromethane,tetrahydrofuran, at a temperature ranging from 0° C. to reflux and for atime ranging from 30 minutes to about 48 hours.

When PG₅ is a resin for solid-phase synthesis the loading can beaccomplished using any suitable resin such as a plystyrene orpolyethylenglycol grafted polystyrene resin provided that they bear asuitable linker. A non-limiting list of such resins include tritylchloride resin, 2-chlorotrityl chloride resin,4-(bromomethyl)phenoxymethyl resin, 4-(bromomethyl)phenoxyethyl resin,Bromo MAMP resin, p-nitrophenyl carbonate Wang resin, p-nitrophenylcarbonate Merrifield resin, 3,4-dihydro-2H-pyran-2-ylmethyoxymethylresin, p-nitrophenyl carbonate buthyloxymethyl resin, and the like. Saidresins are typically reacted with compounds of general formula (II)A ina suitable solvent such as dichloromethane, tetrahydrofuran, toluene,1,2-dimethoxyethane, N,N-dimethylformamide, methanol, or mixturesthereof, optionally in the presence of an opportune proton scavengersuch as triethylamine, K₂CO₃, N,N-diisopropylethylamine, pyridine or thelike, at a temperature ranging from 0° C. to 40° C. and for a timeranging from 30 minutes to about 48 hours. It is clearly understood bythose skilled in the art, that when in said compounds of formula (II) mis 0 and R1 is a protective group as described above, any or even amixture of the regioisomeric compounds of formula (II) and 10 can beused for the forthcoming transformation as said protective group will beremoved at the end of transformation by using any of the procedure knownin the art, providing compounds of general formula (I) wherein m is 0and R1 is hydrogen.

When preparing the compounds of formula (I) according to any variant ofthe process, which are all to be intended as within the scope of theinvention, optional functional groups within the starting materials, thereagents or the intermediates thereof, and which could give rise tounwanted side reactions, need to be properly protected according toconventional techniques.

The starting materials of the process object of the present invention,comprehensive of any possible variant, as well as any reactant thereof,are known compounds and if not commercially available per se may beprepared according to well-known methods.

Pharmacology Assays In Vitro Cell Proliferation Assay

Exponentially growing human melanoma cells A375 (with a mutated B-RAF)and human melanoma cells Mewo (with wild-type B-Raf) were seeded andincubated at 37° C. in a humidified 5% CO₂ atmosphere. After 24 hours,scalar doses of the compound were added to the medium and cellsoncubated for 72 hours. At the end of treatment, cells were washed andcounted. Cell number was determined by a cellular adenosine triphosphatemonitoring system. Cell proliferation was compared to control cells andthe concentration inhibiting cell growth by 50% was calculated.

p-MAPK (T202/Y204) ArrayScan Assay

A375 human melanoma cells, having a mutated B-RAF, are seeded in384-well poly-lysine coated plates (Matrix) at a density of 1000cells/well with appropriate medium supplemented with 10% FCS andincubated for 16-24 hours. Cells are treated for 1.5 or 2 hours withincreasing doses of compounds (starting dose 10 μM, dilution factor2.5). At the end of the treatment cells are fixed with p-formaldehyde3.7% for 15-30 min, then washed twice with D-PBS (80 l/well) andpermeabilized with D-PBS containing 0.1% Triton X-100 and 1% BSA(Sigma-Aldrich) for 15 minutes at room temperature (staining solution).Anti-phospho-MAPK (T202/Y204) monoclonal antibody E10 (Cell Signaling,cat. #9106) diluted 1:100 is added in staining solution and incubatedfor 1 hour at 37° C. After removal of the primary antibody solution, theanti-mouse Cy™2-conjugated (Green) secondary antibody (Amersham) diluted1:500 in staining solution containing 2 μg/ml DAPI is added. The plateis incubated for 1 hour at 37° C., washed twice and then red withCellomics' ArrayScan VTI (4 fields/well, CytoNucTrans algorithm).

The parameter “MEAN_RingAvgIntenCh2”, which measures the meancytoplasmatic fluorescence intensity associated to p-MAPK staining, isreported as the final result.

B-RAF mutations, that constitutively activate the kinase, have beenidentified in the majority of melanoma and a large fraction ofcolorectal and papillary thyroid carcinoma. The growth of cells withactivated B-RAF strictly depends on B-RAF activity.

Given the above assays, the compounds of formula (I) result to posses aremarkable activity in inhibiting cell proliferation, with IC₅₀ valueslower than 10 μM on the cell line with mutated B-Raf (A375), and higheron the cell line with wild-type B-Raf (Mewo), as reported in thefollowing table.

In the same table the data obtained with compounds of formula (I) in theArrayScan assay are also reported and demonstrate the ability of thecompounds of formula (I) to inhibit the signal transduction pathwaycontrolled by B-RAF activation in A375 cell line with mutated B-RAF. TheIC₅₀ values are always lower than 10 μM and are in agreement with theIC₅₀ values obtained in the proliferation assay on the same cell line,confirming that the antiproliferative activity of the compounds is dueto the inhibition of B-RAF activity.

TABLE 1 Proliferation and Array Scan data Proliferation Array Scan Cmpd.A375 IC₅₀ Mewo IC₅₀ A375 IC₅₀ N° Name (μM) (μM) (μM) 11-[3-(4-Pyridin-4-yl-1H-pyrazol- 1.02 8.60 0.93 3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea 2 2,5-Difluoro-N-[3-(4-pyridin-4- 1.40 >100.64 yl-1H-pyrazol-3-yl)-phenyl]- benzenesulfonamide 4N-(4-tert-Butyl-phenyl)-3-(4- 2.31 5.84 1.26pyridin-4-yl-1H-pyrazol-3-yl)- benzamide 51-(4-Chloro-3-trifluoromethyl- 4.31 6.76 2.09phenyl)-3-{3-[1-(2-fluoro-ethyl)- 4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-urea 6 Furan-2-sulfonic acid [3-(4- 7.52 >10 5.47pyridin-4-yl-1H-pyrazol-3-yl)- phenyl]-amide 7 Thiophene-3-sulfonic acid[3- 7.38 >10 5.52 (4-pyridin-4-yl-1H-pyrazol-3-yl)- phenyl]-amide 81-[3-(4-Pyridin-4-yl-1H-pyrazol- 4.48 >10 1.453-yl)-phenyl]-3-p-tolyl-urea 9 1-(4-Chloro-phenyl)-3-[3-(4- 4.10 >104.80 pyridin-4-yl-1H-pyrazol-3-yl)- phenyl]-urea 101-[3-(1-Ethyl-4-pyridin-4-yl-1H- 1.63 7.5 0.54pyrazol-3-yl)-phenyl]-3-(4- trifuoromethyl-phenyl)-urea 111-[3-(1-Cyanomethyl-4-pyridin- 1.13 7.69 0.234-yl-1H-pyrazol-3-yl)-phenyl]-3- (4-trifuoromethyl-phenyl)-urea 121-{3-[4-(2-aminopyridin-4-yl)- 5.96 >10 4.65 1H-pyrazol-3-yl]phenyl}-3-[4(trifluoromethyl)-phenyl]urea 13 1-{3-[1-(2-Fluoro-ethyl)-4- 1.38 8.110.56 pyridin-4-yl-1H-pyrazol-3-yl]- phenyl}-3-(4-trifluoromethyl-phenyl)-urea 14 1-{3-[1-(2-Hydroxy-ethyl)-4- 6.94 >10 2.63pyridin-4-yl-1H-pyrazol-3-yl]- phenyl}-3-(4-trifluoromethyl-phenyl)-urea 16 N-[3-(4-Pyridin-4-yl-1H-pyrazol- 2.89 >10 1.343-yl)-phenyl]-2-(4- trifluoromethyl-phenyl)- acetamide 17N-[4-(3-{3-[3-(4-Trifluoromethyl- 0.25 9.40 <0.04phenyl)-ureido]-phenyl}-1H- pyrazol-4-yl)-pyridin-2-yl]- acetamide 18N-[2,4-Difluoro-3-(4-pyridin-4- 0.72 >10 0.36yl-1H-pyrazol-3-yl)-phenyl]-2,5- difluoro-benzenesulfonamide 19Thiophene-3-sulfonic acid [2,4- 3.17 >10 0.83difluoro-3-(4-pyridin-4-yl-1H- pyrazol-3-yl)-phenyl]-amide 20Furan-2-sulfonic acid [2,4- 9.14 >10 5.48 difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide 21 Propane-1-sulfonic acid [2,4- 4.28 >101.79 difluoro-3-(4-pyridin-4-yl-1H- pyrazol-3-yl)-phenyl]-amide 311-{3-[4-(2-Amino-pyrimidin-4- 2.70 >10 0.73yl)-1H-pyrazol-3-yl]-phenyl}-3- (4-trifluoromethyl-phenyl)-urea 32N-[4-(3-{3-[3-(4-Trifluoromethyl- 5.32 >10 2.51phenyl)-ureido]-phenyl}-1H- pyrazol-4-yl)-pyrimidin-2-yl]- acetamide 34N-{3-[4-(2-Amino-pyrimidin-4- 3.18 >10 0.34yl)-1H-pyrazol-3-yl]-phenyl}- 2,5-difluoro- benzenesulfonamide 39N-[4-(3-{3-[3-(4-Trifluoromethyl- 1.14 >10 2.32phenyl)-ureido]-phenyl}-1H- pyrazol-4-yl)-pyridin-2-yl]- propionamide 40N-[4-(3-{3-[3-(4-Trifluoromethyl- 3.63 >10 1.75phenyl)-ureido]-phenyl}-1H- pyrazol-4-yl)-pyridin-2-yl]- isobutyramide43 4-Hydroxy-N-[4-(3-{3-[3-(4- 3.5 >10 0.41 trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4- yl)-pyridin-2-yl]-butyramide 474-Pyridin-4-yl-3-{3-[3-(4- 2.66 >10 0.75 trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazole-1- carboxylic acid ethyl ester 481-[3-(1-Methyl-4-pyridin-4-yl- 3.86 >10 1.791H-pyrazol-3-yl)-phenyl]-3-(4- trifuoromethyl-phenyl)-urea 491-[3-(1-Butyl-4-pyridin-4-yl-1H- 2.61 4.54 1.59pyrazol-3-yl)-phenyl]-3-(4- trifuoromethyl-phenyl)-urea 501-[3-(1-Isobutyl-4-pyridin-4-yl- 1.9 5.09 1.121H-pyrazol-3-yl)-phenyl]-3-(4- trifluoromethyl-phenyl)-urea 51N-[3-(1-Ethyl-4-pyridin-4-yl-1H- <0.02 >10 <0.01pyrazol-3-yl)-2,4-difluoro- phenyl]-2,5-difluoro- benzenesulfonamide 52N-[2,4-Difluoro-3-(1-methyl-4- 0.16 >10 <0.01pyridin-4-yl-1H-pyrazol-3-yl)- phenyl]-2,5-difluoro- benzenesulfonamide53 N-{2,4-Difluoro-3-[4-(2- 1.75 >10 0.87 methylamino-pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}-2,5- difluoro-benzenesulfonamide 54N-{3-[4-(2-Ethylamino-pyridin- 0.97 >10 0.31 4-yl)-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro- benzenesulfonamide 55N-{3-[4-(2-Ethylamino- 1.25 >10 0.17 pyrimidin-4-yl)-1H-pyrazol-3-yl]-phenyl}-2,5-difluoro- benzenesulfonamide 56N-[2,4-Difluoro-3-(1-isobutyl-4- <0.02 >10 <0.01pyridin-4-yl-1H-pyrazol-3-yl)- phenyl]-2,5-difluoro- benzenesulfonamide57 N-[3-(1-Ethyl-4-pyridin-4-yl-1H- 0.33 >10 0.02pyrazol-3-yl)-2,4-difluoro- phenyl]-2-fluoro- benzenesulfonamide 58N-[3-(1-Ethyl-4-pyridin-4-yl-1H- 0.29 >10 0.04pyrazol-3-yl)-2,4-difluoro- phenyl]-3-fluoro- benzenesulfonamide

From all of the above, the novel compounds of formula (I) of theinvention appear to be particularly advantageous in the therapy ofdiseases caused by deregulated protein kinase activity such as cancer.

The compounds of the present invention can be administered either assingle agents or, alternatively, in combination with known anticancertreatments such as radiation therapy or chemotherapy regimen incombination with, for example, antihormonal agents such asantiestrogens, antiandrogens and aromatase inhibitors, topoisomerase Iinhibitors, topoisomerase II inhibitors, agents that targetmicrotubules, platin-based agents, alkylating agents, DNA damaging orintercalating agents, antineoplastic antimetabolites, other kinaseinhibitors, other anti-angiogenic agents, inhibitors of kinesins,therapeutic monoclonal antibodies, inhibitors of mTOR, histonedeacetylase inhibitors, farnesyl transferase inhibitors, and inhibitorsof hypoxic response.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent within the approved dosagerange. Compounds of formula (I) may be used sequentially with knownanticancer agents when a combination formulation is inappropriate.

The compounds of formula (I) of the present invention, suitable foradministration to a mammal, e.g., to humans, can be administered by theusual routes and the dosage level depends upon the age, weight, andconditions of the patient and administration route.

For example, a suitable dosage adopted for oral administration of acompound of formula (I) may range from about 10 to about 1 g per dose,from 1 to 5 times daily. The compounds of the invention can beadministered in a variety of dosage forms, e.g., orally, in the formtablets, capsules, sugar or film coated tablets, liquid solutions orsuspensions; rectally in the form suppositories; parenterally, e.g.,intramuscularly, or through intravenous and/or intrathecal and/orintraspinal injection or infusion.

The present invention also includes pharmaceutical compositionscomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof in association with a pharmaceutically acceptableexcipient, which may be a carrier or a diluent.

The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a suitable pharmaceutical form.

For example, the solid oral forms may contain, together with the activecompound, diluents, e.g., lactose, dextrose saccharose, sucrose,cellulose, corn starch or potato starch; lubricants, e.g., silica, talc,stearic acid, magnesium or calcium stearate, and/or polyethyleneglycols; binding agents, e.g., starches, arabic gum, gelatinemethylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone;disintegrating agents, e.g., starch, alginic acid, alginates or sodiumto starch glycolate; effervescing mixtures; dyestuffs; sweeteners;wetting agents such as lecithin, polysorbates, laurylsulphates; and, ingeneral, non-toxic and pharmacologically inactive substances used inpharmaceutical formulations. These pharmaceutical preparations may bemanufactured in known manner, for example, by means of mixing,granulating, tabletting, sugar-coating, or film-coating processes.

The liquid dispersions for oral administration may be, e.g., syrups,emulsions and suspensions.

As an example the syrups may contain, as a carrier, saccharose orsaccharose with glycerine and/or mannitol and sorbitol.

The suspensions and the emulsions may contain, as examples of carriers,natural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol.

The suspension or solutions for intramuscular injections may contain,together with the active compound, a pharmaceutically acceptablecarrier, e.g., sterile water, olive oil, ethyl oleate, glycols, e.g.,propylene glycol and, if desired, a suitable amount of lidocainehydrochloride.

The solutions for intravenous injections or infusions may contain, as acarrier, sterile water or preferably they may be in the form of sterile,aqueous, isotonic, saline solutions or they may contain propylene glycolas a carrier. The suppositories may contain, together with the activecompound, a pharmaceutically acceptable carrier, e.g., cocoa butter,polyethylene glycol, a polyoxyethylene sorbitan fatty acid estersurfactant or lecithin.

EXPERIMENTAL SECTION

For a reference to any specific compound of formula (I) of theinvention, optionally in the form of a pharmaceutically acceptable salt,see the experimental section and claims. Referring to the examples thatfollow, compounds of the present invention were synthesized using themethods described herein, or other methods, which are well known in theart.

The short forms and abbreviations used herein have the followingmeaning:

-   g (grams) mg (milligrams)-   ml (milliliters) mM (millimolar)-   μM (micromolar) mmol (millimoles)-   h (hours) MHz (Mega-Hertz)-   mm (millimetres) Hz (Hertz)-   M (molar) min (minutes)-   mol (moles) TLC (thin layer chromatography)-   r.t. (room temperature) TEA (triethylamine)-   TFA (trifluoroacetic acid) DMF (N,N-dimethyl formamide)-   DIPEA (N,N-diisopropyl-N-ethylamine) DCM (dichloromethane)-   THF (tetrahydrofuran) Hex (hexane)-   MeOH (Methanol) DMSO (dimethylsulfoxide)-   TIPS (triisopropylsilyl) bs (broad singlet)-   TBDMS (dimethyl-tert-butylsilyl) BOC (tert-butyloxycarbonyl)-   NaH=sodium hydride, 60% in mineral oil Ac₂O acetic anhydride-   Dppf (1,1′-bis(diphenylphosphino)ferrocene) ESI=electrospray    ionization-   mCPBA (m-chloroperbenzoic acid) Ac (acetyl)-   TBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium    tetrafluoroborate-   RP-HPLC (reverse phase high performance liquid chromatography)

With the aim to better illustrate the present invention, without posingany limitation to it, the following examples are now given.

As used herein the symbols and conventions used in the processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry.

Unless otherwise noted, all materials were obtained from commercialsuppliers, of the best grade and used without further purification.Anhydrous solvent such as DMF, THF, CH₂Cl₂ and toluene were obtainedfrom the Aldrich Chemical Company. All reactions involving air- ormoisture-sensitive compounds were performed under nitrogen or argonatmosphere.

General Purification and Analytical Methods

Flash Chromatography was performed on silica gel (Merck grade 9395,60A). HPLC was performed on Waters X Terra RP 18 (4.6×50 mm, 3.5 μm)column using a Waters 2790 HPLC system equipped with a 996 Waters PDAdetector and Micromass mod. ZQ single quadrupole mass spectrometer,equipped with an electrospray (ESI) ion source. Mobile phase A wasammonium acetate 5 mM buffer (pH 5.5 with acetic acid-acetonitrile95:5), and Mobile phase B was water-acetonitrile (5:95). Gradient from10 to 90% B in 8 minutes, hold 90% B 2 minutes. UV detection at 220 nmand 254 nm. Flow rate 1 mL/min. Injection volume 10 microL. Full scan,mass range from 100 to 800 amu. Capillary voltage was 2.5 KV; sourcetemperature was 120° C.; cone was 10 V. Retention times (HPLC r.t.) aregiven in minutes at 220 nm or at 254 nm. Mass are given as m/z ratio.

When necessary, compounds were purified by preparative HPLC on a WatersSymmetry C18 (19×50 mm, 5 μm) column or on a Waters X Terra RP 18(30×150 mm, 5 μm) column using a Waters preparative HPLC 600 equippedwith a 996 Waters PDA detector and a Micromass mod. ZMD singlequadrupole mass spectrometer, electron spray ionization, positive mode.Mobile phase A was water-0.01% trifluoroacetic acid, and mobile phase Bwas acetonitrile. Gradient from 10 to 90% B in 8 min, hold 90% B 2 min.Flow rate 20 mL/min. In alternative, mobile phase A was water-0.1% NH₃,and mobile phase B was acetonitrile. Gradient from 10 to 100% B in 8min, hold 100% B 2 min.

Flow rate 20 mL/min.

1H-NMR spectrometry was performed on a Mercury VX 400 operating at400.45 MHz equipped with a 5 mm double resonance probe [1H (15N-31P)ID_PFG Varian].

Preparation of 4-[3-(3-nitro-phenyl)-1H-pyrazol-4-yl]-pyridine

[(II)A, X═CH; R2, R3, R4, R5, R6=H; G=NO₂]

Method A Step a: [Hydroxy-(3-nitro-phenyl)methyl]-phosphonic aciddimethyl ester

3-Nitrobenzaldehyde (20 g, 0.132 mol) was dissolved in 100 mL of ethylacetate. Triethylamine (22 mL, 0.158 mol, 1.2 eq) was added, followed bydimethylphosphite (15.7 mL, 0.171 mmol, 1.3 eq) and the mixture wasstirred at room temperature. After 2 hours the mixture was diluted with150 mL of ethyl acetate and washed with saturated aqueous ammoniumchloride (2×50 mL) and water (50 mL). The organic layer was dried overNa₂SO₄ and concentrated under reduced pressure. The residue was treatedwith ethyl ether to obtain a beige solid, which was filtered and driedunder vacuum at 40° C. for 1 h (26.7 g, 77% yield).

HPLC (254 nm): R_(t): 3.15 min.

¹H NMR (401 MHz, DMSO-d₆) δ=8.30 (q, J=1.8 Hz, 1H), 8.14-8.20 (m, 1H),7.89 (d, J=7.6 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 6.62 (dd, J=5.9, 14.1Hz, 1H), 5.30 (dd, J=5.9, 14.0 Hz, 1H), 3.67 (d, J=7.4 Hz, 3H), 3.64 (d,J=7.4 Hz, 3H). HRMS (ESI) calcd for C9H12NO6P [M+H]⁺ 262.0475, found262.0478.

Step b: [(3-Nitro-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-phosphonicacid dimethyl ester

[Hydroxy-(3-nitro-phenyl)-methyl]-phosphonic acid dimethyl ester (26.7g, 0.102 mol) was suspended in dry toluene (340 mL) under nitrogenatmosphere. 3,4-Dihydro-2H-pyrane (20.6 mL, 0.228 mol, 2.2 eq) wasadded, followed by p-toluenesulfonic acid (590 mg, 0.003 mol, 0.03 eq)and the mixture was stirred at 60° C. for 1 h. the reaction mixture wasthen concentrated under reduced pressure, taken up with ethyl acetate(300 mL) and washed with saturated aqueous NaHCO₃ and water. The organiclayer was dried over Na₂SO₄ and concentrated to dryness. The desiredproduct was obtained in quantitative yield as a yellow solid (mixture of2 diastereoisomers).

HPLC (254 nm): R_(t): 4.88 min.

¹H NMR (401 MHz, DMSO-d₆) (major diastereoisomer) δ=8.25 (q, J=2.2 Hz,1H), 8.23 (dt, J=2.5, 8.2 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.70 (t,J=7.9 Hz, 1H), 5.38 (d, J=17.3 Hz, 1H), 4.43 (t, J=2.7 Hz, 1H),3.85-3.97 (m, 1H), 3.73 (d, J=10.5 Hz, 3H), 3.65 (d, J=10.5 Hz, 3H),3.48-3.56 (m, 1H), 1.49-1.82 (3 m, 6H). HRMS (ESI) calcd for C14H20NO7P[M+H]⁺ 346.105, found 346.1043.

Step c:4-[2-(3-Nitro-phenyl)-2-(tetrahydro-pyran-2-yloxy)-vinyl]-pyridine

[(3-Nitro-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-phosphonic aciddimethyl ester (40.7 g, 0.105 mol) was dissolved in dry THF (1 L) undernitrogen. Sodium hydride (60% suspension in mineral oil) (6.3 g, 0.158mol, 1.5 eq) was added and the mixture was stirred for 10 minutes atroom temperature. Neat 4-picolinaldehyde (10 mL, 0.105 mol, 1 eq) wasthen added dropwise and the mixture was heated to 60° C. and stirred atthis temperature for 2.5 hours. The reaction mixture was concentratedunder reduced pressure to ⅓ of the original volume and then diluted withwater (500 mL). pH was adjusted to 7-8 by adding a saturated solution ofNaHCO₃ and the mixture was extracted with ethyl acetate (4×300 mL). Theorganic layer was dried over Na₂SO₄ and concentrated to dryness. An oil(37.7 g) was obtained, which was used without further purification inthe following step.

Step d: 1-(3-Nitro-phenyl)-2-pyridin-4-yl-ethanone

The oil obtained in the previous step was dissolved in methanol (570mL). 1N HCl (57 mL) was added and the mixture was stirred at 50° C. for2 hours. The mixture was then concentrated under reduced pressure anddiluted with water (200 mL). pH was adjusted to 7-8 by addition ofNaHCO₃. The precipitated product was collected by filtration, washedwith water and dried under vacuum at 60° C. for 1 h obtaining 23.7 g ofbrown solid. The solid was purified by flash chromatography on silicagel (ethyl acetate) and then treated with ethyl ether to obtain anoff-white solid, which was dried under vacuum at 40° C. for 1 h (15 g,59% yield over three steps).

HPLC (254 nm): R_(t): 4.29 min.

¹H NMR (401 MHz, DMSO-d₆) δ=8.74 (t, J=1.8 Hz, 1H), 8.52-8.55 (m, 2H),8.52 (m, 1H), 8.49 (m, 1H), 7.89 (t, J=7.8 Hz, 1H), 7.30-7.34 (m, 2H),4.63 (s, 2H).

HRMS (ESI) calcd for C13H10N2O3 [M+H]⁺ 243.0764, found 243.0772.

Step f: (E)-3-Dimethylamino-1-(3-nitro-phenyl)-2-pyridin-4-yl-propenone

1-(3-Nitro-phenyl)-2-pyridin-4-yl-ethanone (6 g, 24.77 mmol) wasdissolved in dry toluene (240 mL) under nitrogen atmosphere,dimethylformamidedimethylacetal (13.2 mL, 99.36 mmol, 4 eq) was addedand the mixture was heated to 80° C. and stirred for 2 hours. Thereaction mixture was then evaporated to dryness and kept under highvacuum for 2 hours. The crude (7.44 g) was obtained as oil and was usedas is in the following step.

HPLC (254 nm): R_(t): 3.57 min.

¹H NMR (401 MHz, DMSO-d₆) δ=8.44 (br. s., 2H), 8.26 (ddd, J=1.0, 2.3,8.2 Hz, 1H), 8.14 (br. s., 1H), 7.80 (d, J=7.4 Hz, 1H), 7.66 (t, J=7.9Hz, 1H), 7.36 (s, 1H), 7.16 (br. s., 2H), 2.75 (br. s., 6H).

HRMS (ESI) calcd for C16H15N3O3 [M+H]⁺ 298.1186, found 298.1188.

Step g: 4-[3-(3-Nitro-phenyl)-1H-pyrazol-4-yl]-pyridine [(II)A, X═CH,R′, R3, R4, R5, R6=H, G=NO₂]

Crude (E)-3-Dimethylamino-1-(3-nitro-phenyl)-2-pyridin-4-yl-propenone(24.77 mmol) was dissolved in a hydrazine solution 1M in THF (100 mL,100 mmol, 4 eq) under nitrogen atmosphere and the mixture was heated to70° C. and stirred at this temperature for 2 hours. The mixture was thenallowed to cool to room temperature and then kept at 4° C. for 2 hours.The crystallized solid was collected by filtration and dried at 40° C.under vacuum for 2 hours. 4.88 g (74% yield over two steps) of4-[3-(3-nitro-phenyl)-1H-pyrazol-4-yl]-pyridine were obtained asoff-white solid.

HPLC (254 nm): R_(t): 3.88 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.53 (br. s., 1H), 8.50 (d, J=5.9 Hz, 2H),8.29 (s, 1H), 8.25 (s, 1H), 8.23 (m, 1H), 7.86 (dd, J=2.0, 7.2 Hz, 1H),7.70 (t, J=7.9 Hz, 1H), 7.29 (d, J=6.1 Hz, 2H). HRMS (ESI) calcd forC14H10N4O2 [M+H]+267.0877, found 267.0883.

Example 11-(2,4-Difluoro-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=2,4-difluorophenyl]

Method N Step a

4-[3-(3-Nitro-phenyl)-1H-pyrazol-4-yl]-pyridine (9.5 mmol) and DIPEA(3.26 ml, 19.5 mmol) and were added to a slurry of trityl chloride resin(5 g, 1.27 mmol/g loading, 6.35 mmol) in DCM (50 ml). The mixture wasgently stirred at rt for 24 h and then filtered under reduced pressure.The resin was suspended in a mixture of DCM/MeOH/DIPEA 85:10:5 (100 ml),stirred for 20 min and filtered. After washing consecutively with DCM,DMF and MeOH, it was dried overnight in the oven at 35° C. under reducedpressure. The resin gave rise to a loading of 1 mmol/g measured byweight increase.

Method G Step a

A solution of SnCl₂*H₂O (6.6 g, 30 mmol) in DMF (10 ml) was added to aslurry of the resin obtained in the previous step (2 g, 2 mmol) in DMF(10 ml). The suspension was stirred at r.t. for 48 h. After filteringunder reduced pressure the resin was washed with DMF (3×), DCM (3×),MeOH (3×) and Et2O (3×) and dried at 35° C. under vacuum.

Step e

The appropriate isocyanate (0.04 mmol) was added to the resin obtainedin Step a (100 mg, 0.01 mmol), swelled in DCM (3 ml) in the Questvessel. The resulting suspension was stirred for 20 h at r.t., filtered,washed with DCM, DMF and MeOH, dried under nitrogen flux and used in thenext step.

Method M Step a

A solution of 2 ml of TFA 20% in DCM was added to 100 mg of the resinobtained in Step d in the Quest vessels. The red suspension was stirredfor 1 h then filtered and the resin washed twice with 1 ml of DCM. Thefiltered solution was evaporated under nitrogen flux to give the productas an oil, which was purified by preparative HPLC.

HPLC (254 nm): R_(t): 4.43 min

¹H NMR (401 MHz, DMSO-d₆), δ=13.55 (br s, 1H), 9.15 (s, 1H), 8.63 (d,J=6.5 Hz, 2H), 8.51 (s, 1H), 8.41 (br. s., 1H), 8.03 (td, J=6.2, 9.2 Hz,1H), 7.66 (d, J=6.5 Hz, 2H), 7.61 (t, J=1.8 Hz, 1H), 7.49-7.55 (m, 1H),7.37-7.44 (m, 1H), 7.31 (ddd, J=2.9, 8.9, 11.6 Hz, 1H), 6.99-7.10 (m,2H). HRMS (ESI) calcd for C₂₁H₁₆F₂N₅O [M+H]⁺ 392.1318, found 392.1308.

Operating in an analogous way the following compounds were obtained:

1-Naphthalen-1-yl-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=naphthalene-1-yl]

HPLC (254 nm): R_(t): 4.64 min

¹H NMR (401 MHz, DMSO-d₆), δ=13.41 and 13.26 (2br s, 1H, tautomers),9.15 (br s, 1H), 8.75 (br s, 1H), 8.47 (d, J=6.1 Hz, 2H), 8.27 (br s,1H), 8.11 (d, J=8.2 Hz, 1H), 7.93-7.93 (m, 3H), 7.56-7.66 (m, 6H),7.45-7.50 (m, 1H), 7.31 (br. s., 2H).

HRMS (ESI) calcd for C₂₅H₁₉N₅O [M+H]⁺ 406.1663, found 406.1655.

1-(3-Chloro-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=3-chloro-phenyl]

HPLC (254 nm): R_(t): 4.72 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.45 and 13.31 (2br s, 1H, tautomers),8.86 (br s, 2H), 8.47 (d, J=6.0 Hz, 2H), 8.27 and 7.96 (2br s, 1H,tautomers), 7.69 (t, J=2.0 Hz, 1H), 7.24-7.53 (m, 8H), 7.00-7.04 (m,1H). HRMS (ESI) calcd for C₂₁H₁₆ClN₅O [M+H]⁺ 390.1116, found 390.1104.

1-(3-Methoxy-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=3-methoxy-phenyl]

HPLC (254 nm): R_(t): 4.22 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.39 and 13.28 (2br s, 1H, tautomers),8.68 (m, 2H), 8.43-8.48 (m, 2H), 8.25 and 7.96 (2br s, 1H, tautomers),7.39-7.53 (m, 4H), 7.29 (br s, 2H), 7.14-7.20 (m, 2H), 6.91 (ddd, J=0.9,1.2, 7.2 Hz, 1H), 6.56 (dd, J=1.9, 8.2 Hz, 1H), 3.73 (s, 3H). HRMS (ESI)calcd for C₂₂H₁₉N₅O₂ [M+H]⁺ 386.1612, found 386.1604.

1-(3-Fluoro-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=3-fluoro-phenyl]

HPLC (254 nm): R_(t): 4.40 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.40 and 13.28 (2br s, 1H, tautomers),8.86 (br s, 2H), 8.47 (d, J=6.0 Hz, 2H), 8.25 and 7.96 (2br s, 1H,tautomers), 7.48-7.52 (m, 1H), 7.47 (dt, J=2.2, 12.2 Hz, 1H), 7.27-7.33(m, 5H), 7.11 (dd, J=1.2, 8.3 Hz, 1H), 6.75-6.83 (m, 2H). HRMS (ESI)calcd for C₂₁H₁₆FN₆O [M+H]⁺ 374.1412, found 374.1407.

1-(4-Fluoro-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=4-fluoro-phenyl]

HPLC (254 nm): R_(t): 4.30 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.44 (br s, 1H), 8.79 (br s, 1H), 8.71 (brs, 1H), 8.53 (d, J=6.1 Hz, 2H), 8.26 (br s, 1H), 7.56 (s, 1H), 7.37-7.48(m, 6H), 7.07-7.16 (m, 2H), 7.03 (d, J=6.2 Hz, 1H). HRMS (ESI) calcd forC₂₁H₁₆FN₅O [M+H]⁺ 374.1412, found 374.1407.

1-(2,6-Dimethyl-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=2,6-dimethyl-phenyl]

HPLC (254 nm): R_(t): 4.54 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.40 (br. s., 1H), 8.86 (br s, 2H), 8.52(d, J=6.0 Hz, 2H), 8.28 (br. s., 1H), 7.37-7.77 (m, 4H), 7.44 (d, J=6.0Hz, 2H), 6.97-7.09 (m, 3H), 2.20 (s, 6H). HRMS (ESI) calcd for C₂₃H₂₁N₅O[M+H]⁺ 384.1819, found 384.1810.

1-(2-Methoxy-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=2-methoxy-phenyl]

HPLC (254 nm): R_(t): 4.76 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.48 (s, 1H), 9.42 (br. s., 1H), 8.52-8.59(m, 2H), 8.22 (s, 1H), 8.09 (dd, J=1.7, 7.9 Hz, 1H), 7.58 (d, J=1.6 Hz,1H), 7.38-7.53 (m, 4H), 7.04 (d, J=7.8 Hz, 1H), 7.02 (dd, J=1.5, 8.0 Hz,1H), 6.95 (td, J=1.7, 7.7 Hz, 1H), 6.85-6.92 (m, 1H), 3.88 (s, 3H). HRMS(ESI) calcd for C₂₂H₁₉N₅O₂ [M+H]⁺ 386.1612, found 386.1608.

1-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethoxy-phenyl)-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H;R7=4-trifluoromethoxy-phenyl]

HPLC (254 nm): R_(t): 4.24 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.39 and 13.28 (2br s, 1H, tautomers),8.83 (br s, 2H), 8.44-8.49 (m, 2H), 8.25 and 7.96 (2br s, 1H,tautomers), 7.50-7.56 (m, 5H), 7.26-7.31 (m, 4H), 7.02 (m, 1H). HRMS(ESI) calcd for C₂₂H₁₆F₃N₅O₂ [M+H]⁺ 440.1329, found 440.1318.

1-(3,4-Difluoro-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=3,4-difluoro-phenyl]

HPLC (254 nm): R_(t): 4.54 min

¹H NMR (401 MHz, DMSO-d₆), δ=13.39 and 13.28 (2br s, 1H, tautomers),8.84 (br s, 2H), 8.44-8.49 (m, 2H), 8.25 and 7.96 (2br s, 1H,tautomers), 7.64 (m, 1H), 7.28-7.50 (m, 6H), 7.09-7.13 (m, 1H), 7.02 (m,1H). HRMS (ESI) calcd for C₂₁H₁₆F₂N₅O [M+H]⁺ 392.1318, found 392.1312.

1-(2,6-Diethyl-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=2,6-diethyl-phenyl]

HPLC (254 nm): R_(t): 4.76 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.36 and 13.25 (2br s, 1H, tautomers),8.78 (br s, 2H), 8.42-8.46 (m, 2H), 8.23 and 7.95 (2br s, 1H,tautomers), 7.28-7.50 (m, 5H), 7.13-7.22 (m, 1H), 7.07-7.13 (m, 2H),6.95 (m, 1H), 2.53-2.61 (m, 4H), 1.13 (t, J=7.6 Hz, 6H). HRMS (ESI)calcd for C₂₅H₂₅N₅O [M+H]⁺ 412.2132, found 412.2121.

3-{3-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-ureido}-benzoic acidmethyl ester

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H;R7=3-carbomethoxy-phenyl]

HPLC (254 nm): R_(t): 4.24 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.40 and 13.28 (2br s, 1H, tautomers),8.76-8.91 (m, 2H), 8.44-8.48 (m, 2H), 8.25 and 7.96 (2br s, 1H,tautomers), 8.19 (t, J=1.8 Hz, 1H), 7.61 (ddd, J=1.1, 2.2, 8.1 Hz, 1H),7.55-7.59 (m, 1H), 7.50-7.55 (m, 3H), 7.43 (t, J=7.9 Hz, 1H), 7.29 (br.s., 2H), 7.02 (m, 1H), 3.86 (s, 3H). HRMS (ESI) calcd for C₂₃F₁₉N₅O₃[M+H]⁺ 414.1561, found 414.1549.

1-(3-Acetyl-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=3-acetyl-phenyl]

HPLC (254 nm): R_(t): 3.95 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.41 and 13.28 (2br s, 1H, tautomers),8.75-8.95 (m, 2H), 8.43-8.49 (m, 2H), 8.27 and 7.97 (2br s, 1H,tautomers), 8.06 (t, J=1.8 Hz, 1H), 7.63-7.69 (m, 1H), 7.59 (d, J=7.8Hz, 1H), 7.50-7.56 (m, 3H), 7.44 (t, J=7.9 Hz, 1H), 7.28 (br. s., 2H),7.02 (m, 1H), 2.57 (s, 3H). HRMS (ESI) calcd for C₂₃H₁₉N₅O₂ [M+H]⁺398.1612, found 398.1601.

1-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-m-tolyl-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=3-methyl-phenyl]

HPLC (254 nm): R_(t): 4.47 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.38 and 13.27 (2br s, 1H, tautomers),8.53-8.77 (m, 2H), 8.42-8.49 (m, 2H), 8.24 and 7.96 (2br s, 1H,tautomers), 7.48-7.56 (m, 4H), 7.28 (br. s., 2H), 7.21 (d, J=7.8 Hz,1H), 7.15 (t, J=7.9 Hz, 1H), 7.02 (m, 1H), 6.79 (d, J=7.6 Hz, 1H), 2.28(s, 3H). HRMS (ESI) calcd for C₂₂H₁₆N₅O [M+H]⁺ 370.1663, found 370.1660.

1-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-o-tolyl-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=2-methyl-phenyl]

HPLC (254 nm): R_(t): 4.26 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.39 and 13.28 (2br s, 1H, tautomers),8.95-9.18 (m, 1H), 8.43-8.49 (m, 2H), 8.25 and 7.98 (2br s, 1H,tautomers), 7.90-7.99 (m, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.35-7.61 (m,3H), 7.29 (br. s., 2H), 7.18 (d, J=7.4 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H),6.96-7.05 (m, 1H), 6.92-6.98 (m, 1H), 2.23 (s, 3H). HRMS (ESI) calcd forC₂₂H₁₉N₅O [M+H]⁺ 370.1663, found 370.1656.

1-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H;R7=3-trifluoromethyl-phenyl]

HPLC (254 nm): R_(t): 5.03 min

¹H NMR (401 MHz, DMSO-d₆), δ=13.40 and 13.29 (2br s, 1H, tautomers),8.83-9.04 (m, 2H), 8.46 (d, J=6.0 Hz, 2H), 8.25 and 7.96 (2br s, 1H,tautomers), 8.00 (s, 1H), 7.48-7.57 (m, 5H), 7.26-7.33 (m, 3H),6.99-7.07 (m, 1H). HRMS (ESI) calcd for C₂₂H₁₆F₃N₅O [M+H]⁺ 424.1380,found 424.1369.

1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H;R7=2-fluoro-5-trifluoromethyl-phenyl]

HPLC (254 nm): R_(t): 6.03 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.41 and 13.29 (2br s, 1H, tautomers),9.27 and 9.19 (2br s, 1H, tautomers), 8.89 and 8.84 (2br s, 1H,tautomers), 8.58 (d, J=6.7 Hz, 1H), 8.45 (d, J=6.1 Hz, 2H), 8.24 and7.95 (2br s, 1H, tautomers), 7.25-7.62 (m, 7H), 7.01-7.10 (m, 1H). HRMS(ESI) calcd for C₂₂H₁₅F₄N₅O [M+H]⁺ 442.1286, found 442.1267.

1-(3-Phenoxy-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=3-phenoxy-phenyl]

HPLC (254 nm): R_(t): 6.16 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.38 and 13.27 (2br s, 1H, tautomers),8.65-8.81 (m, 2H), 8.45 (d, J=6.0 Hz, 2H), 8.24 and 7.95 (2br s, 1H,tautomers), 7.37-7.44 (m, 2H), 7.24-7.30 (m, 3H), 7.22 (t, J=2.1 Hz,1H), 7.10-7.18 (m, 2H), 6.96-7.06 (m, 4H), 6.59-6.64 (m, 1H). HRMS (ESI)calcd for C₂₇H₂₁N₅O₂ [M+H]⁺ 448.1768, found 448.1752.

1-(3,5-Difluoro-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=3,5-difluoro-phenyl]

HPLC (254 nm): R_(t): 5.56 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.40 and 13.29 (2br s, 1H, tautomers),9.09 and 9.04 (2br s, 1H, tautomers), 8.97 and 8.88 (2br s, 1H,tautomers), 8.43-8.47 (m, 2H), 8.25 and 7.96 (2br s, 1H, tautomers),7.25-7.62 (m, 5

H), 7.14-7.21 (m, 2H), 7.01-7.10 (m, 1H), 6.75-6.83 (m, 2H). HRMS (ESI)calcd for C₂₁H₁₆F₂N₅O [M+H]⁺ 392.1318, found 392.1315.

1-(4-Cyano-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=4-cyano-phenyl]

HPLC (254 nm): R_(t): 5.05 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.40 and 13.29 (2br s, 1H, tautomers),9.20 and 9.15 (2br s, 1H, tautomers), 8.99 and 8.90 (2br s, 1H,tautomers), 8.44-8.48 (m, 2H), 8.25 and 7.96 (2br s, 1H, tautomers),7.70-7.75 (m, 2

H), 7.59-7.64 (m, 2H), 7.25-7.56 (m, 5H), 7.01-7.10 (m, 1H). HRMS (ESI)calcd for C₂₂H₁₆N₆O [M+H]⁺ 381.1459, found 381.1452.

1-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-p-tolyl-urea (Cpnd. 8)

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=4-methyl-phenyl]

HPLC (254 nm): R_(t): 5.35 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.39 and 13.28 (2br s, 1H, tautomers),8.48-8.64 (m, 2H), 8.44-8.48 (m, 2H), 8.25 and 7.97 (2s, 1H, tautomers),7.26-7.70 (m, 7H), 7.08 (d, J=8.0 Hz, 2H), 6.95-7.05 (m, 1H), 2.25 (s,3H). HRMS (ESI) calcd for C₂₂H₁₆N₅O [M+H]⁺ 370.1663, found 370.1680.

1-(4-Chloro-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea(Cpnd. 9)

[(I)E, X═CH, R1, R2, R3, R4, R5, R6=H, m=0, Y═H; R7=4-chloro-phenyl]

HPLC (254 nm): R_(t): 5.57 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.40 and 13.29 (2br s, 1H, tautomers),8.71-8.85 (m, 2H), 8.45-8.50 (m, 2H), 8.26 and 7.97 (2s, 1H, tautomers),7.25-7.63 (m, 9H), 6.97-7.08 (m, 1H). HRMS (ESI) calcd for C₂₁H₁₆ClN₅O[M+H]⁺ 390.1116, found 390.1131.

1-Biphenyl-4-yl-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=4-phenyl-phenyl]

HPLC (254 nm): R_(t): 6.10 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.40 and 13.28 (2br s, 1H, tautomers),8.72-8.86 (m, 2H), 8.46 (d, J=6.0 Hz, 2H), 8.26 and 7.97 (2s, 1H,tautomers), 7.57-7.66 (m, 4H), 7.51-7.56 (m, 2H), 7.41-7.47 (m, 3H),7.27-7.35 (m, 3H), 6.97-7.06 (m, 1H). HRMS (ESI) calcd for C₂₇H₂₁N₅O[M+H]⁺ 432.1819, found 432.1833.

1-Benzyl-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=benzyl]

HPLC (254 nm): R_(t): 4.93 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.35 and 13.25 (2br s, 1H, tautomers),8.54-8.76 (m, 1H), 8.40-8.50 (m, 2H), 8.24 and 7.95 (2s, 1H, tautomers),7.20-7.57 (m, 10H), 6.88-6.97 (m, 1H), 6.54-6.68 (m, 1H), 4.29 (d, J=5.9Hz, 2H). HRMS (ESI) calcd for C22H19N₅O [M+H]⁺ 370.1663, found 370.1681.1-(4-Dimethylamino-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H;R7=4-dimethylamino-phenyl]

HPLC (254 nm): R_(t): 5.03 min.

¹H NMR (401 MHz, DMSO-d₆), δ=8.73 (br s, 1H), 8.60 (d, J=6.6 Hz, 2H),8.43 (br s, 1H), 7.56-7.61 (m, 3H), 7.50-7.54 (m, 1H), 7.33-7.40 (m,1H), 7.28 (d, J=8.9 Hz, 2H), 7.02 (d, J=7.8 Hz, 1H), 6.79 (d, J=7.0 Hz,2H), 2.87 (s, 6H). HRMS (ESI) calcd for C₂₃H₂₂N₅O [M+H]⁺ 399.1928, found399.1931.

1-(2-Fluoro-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=2-fluoro-phenyl]

HPLC (254 nm): R_(t): 5.21 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.41 and 13.29 (2br s, 1H, tautomers),9.10 (br s, 1H), 8.45-8.52 (m, 3H), 8.25 and 7.96 (2br s, 1H,tautomers), 7.50-7.62 (m, 1H), 7.27-7.33 (m, 2H), 7.21-7.26 (m, 1H),7.11-7.17 (m, 1H), 6.97-7.07 (m, 5H). HRMS (ESI) calcd for C₂₁H₁₆FN₅O[M+H]⁺ 374.1412, found 374.1419.

1-(4-Phenoxy-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=4-phenoxy-phenyl]

HPLC (254 nm): R_(t): 6.08 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.40 and 13.28 (2br s, 1H, tautomers),8.60-8.80 (m, 2H), 8.43-8.47 (m, 2H), 8.25 and 7.96 (2br s, 1H,tautomers), 7.49-7.55 (m, 2H), 7.46 (d, J=9.0 Hz, 2H), 7.37 (dd, J=7.4,8.7 Hz, 1H), 7.27-7.32 (m, 2H), 7.05-7.14 (m, 1H), 6.89-7.01 (m, 5H).HRMS (ESI) calcd for C₂₇H₂₁N₅O₂ [M+H]⁺ 448.1768, found 448.1772.

1-Benzo[1,3]dioxol-5-yl-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H;R7=1-benzo[1,3]dioxol-5-yl]

HPLC (254 nm): R_(t): 4.94 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.40 and 13.28 (2br s, 1H, tautomers),8.50-8.76 (m, 2H), 8.43-8.48 (m, 2H), 8.28 and 7.97 (2br s, 1H,tautomers), 7.25-7.60 (m, 5H), 7.18 (d, J=2.0 Hz, 1H), 6.96-7.05 (m,1H), 6.81-6.86 (m, 1H), 6.72-6.79 (m, 1H), 5.97 (s, 2H). HRMS (ESI)calcd for C₂₂H₁₇N₅O₃ [M+H]⁺ 400.1404, found 400.1412.

1-Phenyl-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=phenyl]

HPLC (254 nm): R_(t): 4.18 min.

1H NMR (401 MHz, DMSO-d₆) δ=13.38 and 13.27 (2br. s., 1H, tautomers),8.60-8.85 (m, 2H), 8.45 (dd, J=1.5, 4.6 Hz, 2H), 8.24 and 7.95 (2br. s.,1H, tautomers), 7.33-7.60 (m, 4H), 7.22-7.33 (m, 6H), 6.97 (q, J=7.3 Hz,1H). HRMS (ESI) calcd for C₂₁H₁₇N₅O [M+H]⁺ 356.1506, found 356.1516

1-Isopropyl-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=isopropyl]

HPLC (254 nm): R_(t): 3.84 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.27 (br. s., 1H), 8.43 (d, J=6.0 Hz, 2H),8.28 (br.s., 1H), 8.20 and 7.95 (2br. s., 1H, tautomers), 7.47 (br. s.,1H), 7.42 (t, J=1.7 Hz, 1H), 7.26 (d, J=5.7 Hz, 2H), 6.90 (d, J=6.8 Hz,1H), 6.00 (br. s., 1H), 3.66-3.79 (m, 1H), 1.08 (d, J=6.5 Hz, 6H). HRMS(ESI) calcd for C₁₈H₁₉N₅O [M+H]⁺ 322.1663, found 322.1666

1-(4-Methoxy-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=4-methoxyphenyl]

HPLC (254 nm): R_(t): 4.12 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.37 and 13.26 (2br. s., 1H, tautomers),8.48-8.85 (m, 2H), 8.44 (d, J=6.1 Hz, 2H), 8.23 and 7.95 (2br. s., 1H,tautomers), 7.33 (d, J=9.0 Hz, 2H), 7.27 (d, J=3.8 Hz, 2H), 6.98 (br.s., 1H), 6.84-6.87 (m, 2H), 3.71 (s, 3H). HRMS (ESI) calcd forC₂₂H₁₉N₅O₂ [M+H]⁺ 386.1612, found 386.1615

4-{3-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-ureido}-benzoic acidethyl ester

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=4-carbethoxyphenyl]

HPLC (254 nm): R_(t): 4.69 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.40 and 13.28 (2br. s., 1H, tautomers),9.08 (br. s., 1H), 8.86 (br. s., 1H), 8.46 (d, J=6.0 Hz, 2H), 8.25 and7.92 (2br. s., 1H, tautomers), 7.89 (d, J=8.9 Hz, 2H), 7.57 (d, J=8.9Hz, 2H), 7.25-7.35 (m, 2H), 6.93-7.11 (m, 1H), 4.28 (q, J=7.2 Hz, 2H),1.32 (t, J=7.2 Hz, 3H). HRMS (ESI) calcd for C₂₄H₂₁N₅O₃ [M+H]⁺ 428.1717,found 428.1723

1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H;R7=4-chloro-3-trifluoromethyl-phenyl]

HPLC (254 nm): R_(t): 5.44 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.42 and 13.30 (2br. s., 1H, tautomers),9.03-9.28 (m, 1H), 8.93 (d, J=20.0 Hz, 1H), 8.46 (d, J=6.1 Hz, 2H),8.06-8.12 (m, 1H), 7.54-7.68 (m, 2H), 7.31 (d, J=4.9 Hz, 2H), 7.05 (br.s., 1H). HRMS (ESI) calcd for C₂₂H₁₅ClF₃N₅O [M+H]⁺ 458.0990, found 428.458.0991.

Example 24-Methoxy-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-methoxy-phenyl]

The above sulfonamide was prepared in an analogous way according toMethods G and M using a solid phase approach. The amino derivativeimmobilized on the resin obtained as described in Example 1 wasderivatized and then cleaved from the resin as described below.

Method G Step c

A solution of DIPEA (103 μL, 0.06 mmol) and the appropriate sulfonylchlorides (0.06 mmol) in 2 ml of DCM was added to a suspension of theresin obtained in Step a (Method G) (Example 2) (100 mg, 0.01 mmol) inDCM (1 ml).

The obtained suspension was stirred for 20 h at r.t., filtered, washedwith DCM, DMF and MeOH, dried under nitrogen flux and used in the nextstep.

Method M Step a

A solution of 2 mL of TFA 20% in DCM were added to 100 mg of the resinsobtained in Step b in the Quest vessels. The red suspension was stirredfor 1 h then filtered and the resin washed twice with 1 ml of DCM. Thefiltered solution was evaporated under nitrogen flux to give the productas a crude solid, which was purified by preparative HPLC.

HPLC (254 nm): R_(t): 4.01 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.27 (br s., 1H), 10.25 (br s., 1H), 8.40(d, J=6.0 Hz, 2H), 8.17 (br s., 1H), 7.62 (d, J=8.8 Hz, 2H), 7.17-7.30(m, 1H), 7.15 (d, J=6.0 Hz, 2H), 6.60-7.12 (m, 5H), 3.79 (s, 3H). HRMS(ESI) calcd for C₂₁H₁₈N₄O₃S [M+H]⁺ 407.1173, found 407.1159.

Operating in an analogous way the following compounds were obtained:

4-Methyl-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-methyl-phenyl]

HPLC (254 nm): R_(t): 4.20 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.27 (br s., 1H), 10.26 (br s., 1H), 8.39(d, J=6.1 Hz, 2H), 8.19 (br s., 1H), 7.58 (d, J=8.2 Hz, 2H), 7.26-7.32(m, 2H), 7.19-7.25 (m, 1H), 7.15 (d, J=6.1 Hz, 2H), 6.60-7.12 (m, 3H),2.33 (s, 3H).

HRMS (ESI) calcd for C21H18N4O₃S [M+H]⁺ 391.1223, found 391.1215

3-Methyl-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=3-methyl-phenyl]

HPLC (254 nm): R_(t): 4.17 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.27 (br s., 1H), 13.27 (br s., 1H), 10.31(s, 1H), 8.37-8.42 (m, 2H), 8.20 (br. s., 1H), 7.53 (s, 1H), 7.46-7.51(m, 1H), 7.33-7.41 (br s., 2H), 7.19-7.29 (m, 1H), 7.14-7.18 (m, 2H),6.90-7.12 (m, 3H), 2.32 (s, 3H). HRMS (ESI) calcd for C₂₁H₁₈N₄O₂S [M+H]⁺391.1223, found 391.1211.

3-Methoxy-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=3-methoxy-phenyl]

HPLC (254 nm): R_(t): 4.04 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.28 (br. s., 1H), 10.34 (br. s., 1H),8.38-8.41 (m, 2H), 8.20 (br. s., 1H), 7.40-7.45 (m, 1H), 7.20-7.29 (m,3H), 7.14-7.17 (m, 3H), 6.97-7.05 (m, 2H), 3.75 (s, 3H). HRMS (ESI)calcd for C₂₁H₁₈N₄O₃S [M+H]⁺ 407.1173, found 407.1157.

5-Isoxazol-3-yl-thiophene-2-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0;R7′=5-isoxazol-3-yl-thiophen-2-yl]

HPLC (254 nm): R_(t): 4.50 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.39 and 13.30 (2br s, 1H, tautomers),10.72 (br. s., 1H), 8.71 (d, J=2.0 Hz, 1H), 8.35-8.46 (m, 2H), 8.21 and7.92 (2br s, 1H, tautomers), 7.68 (d, J=3.9 Hz, 1H), 7.56 (d, J=3.9 Hz,1H), 7.21-7.45 (m, 4H), 7.14-7.20 (m, 2H), 7.07 (d, J=2.0 Hz, 1H). HRMS(ESI) calcd for C₂₁H₁₅N₅O₃S₂ [M+H]⁺ 450.0689, found 450.0677.

4-Fluoro-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-fluoro-phenyl]

HPLC (254 nm): R_(t): 4.13 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.28 (br. s., 1H), 10.39 (br. s., 1H),8.41 (d, J=5.8 Hz, 2H), 8.20 (br. s., 1H), 7.73-7.79 (m, 2H), 7.36-7.40(m, 2H), 7.07-7.30 (m, 6H). HRMS (ESI) calcd for C₂₀H₁₅FN₄O₂S [M+H]⁺395.0973, found 395.0969.

4-Nitro-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-nitro-phenyl]

HPLC (254 nm): R_(t): 4.11 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.28 (br. s., 1H), 10.70 (br. s., 1H),8.32-8.41 (m, 4H), 8.20 (br. s., 1H), 7.93-7.96 (m, 2H), 7.05-7.31 (m,6H). HRMS (ESI) calcd for C₂₀H₁₅N₅O₄S [M+H]⁺ 422.0918, found 422.0914.

3-Fluoro-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=3-fluoro-phenyl]

HPLC (254 nm): R_(t): 4.37 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.28 (br. s., 1H), 10.48 (br. s., 1H),8.39-8.42 (m, 2H), 8.21 (br. s., 1H), 7.46-7.64 (m, 4H), 7.06-7.31 (m,6H). HRMS (ESI) calcd for C₂₀H₁₅FN₄O₂S [M+H]⁺ 395.0973, found 395.0961.

2-Fluoro-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=2-fluoro-phenyl]

HPLC (254 nm): R_(t): 3.98 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.27 (br. s., 1H), 10.69 (br. s., 1H),8.38-8.42 (m, 2H), 8.38-8.42 (m, 2H), 8.20 (br. s., 1H), 7.60-7.80 (m,2H), 7.00-7.41 (m, 8H). HRMS (ESI) calcd for C₂₀H₁₅FN₄O₂S [M+H]⁺395.0973, found 395.0955.

4-Cyano-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-cyano-phenyl]

HPLC (254 nm): R_(t): 4.20 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.29 (br. s., 1H), 10.63 (br. s., 1H),8.40-8.44 (m, 2H), 8.20 (br. s., 1H), 8.03 (d, J=8.3 Hz, 2H), 7.85 (d,J=8.3 Hz, 2H), 7.06-7.40 (m, 6H). HRMS (ESI) calcd for C₂₁H₁₆N₅O₂S[M+H]⁺ 402.1019, found 402.1015.

1,2-Dimethyl-1H-imidazole-4-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=;R7′=1,2-dimethyl-1H-imidazol-4-yl]

HPLC (254 nm): R_(t): 3.06 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.27 (br. s., 1H), 10.19 (br. s., 1H),8.41 (d, J=5.9 Hz, 2H), 8.22 (br. s., 1H), 7.63 (s, 1H), 6.95-7.40 (m,6H), 3.53 (s, 3H), 2.25 (s, 3H). HRMS (ESI) calcd for C₁₉H₁₈N₆O₂S [M+H]⁺395.1285, found 395.1274.

6-Chloro-imidazo[2,1-b]thiazole-5-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0;R7′=6-chloro-imidazo[2,1-b]thiazol-5-yl]

HPLC (254 nm): R_(t): 3.82 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.26 (br. s., 1H), 8.38-8.40 (m, 2H), 8.20(br. s., 1H), 7.88-7.92 (m, 1H), 7.55-7.60 (m, 1H), 6.88-7.30 (m, 5H).HRMS (ESI) calcd for C₁₉H₁₃ClN₆O₂S₂ [M+H]⁺ 457.0303, found 457.0295.

4-Acetyl-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-acetyl-phenyl]

HPLC (254 nm): R_(t): 4.15 min

¹H NMR (401 MHz, DMSO-d₆), δ=13.28 (br. s., 1H), 10.55 (br. s., 1H),8.36-8.45 (m, 2H), 8.20 (br. s., 1H), 8.09-8.09 (m, 2H), 7.83 (d, J=8.4Hz, 2H), 7.05-7.39 (m, 6H), 2.60 (s, 3H). HRMS (ESI) calcd forC₂₂H₁₈N₄O₃S [M+H]⁺ 419.1173, found 419.1163.

5-Bromo-thiophene-2-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=5-bromo-thiophen-2-yl]

HPLC (254 nm): R_(t): 5.07 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.31 (br. s., 1H), 10.62 (br. s., 1H),8.41-8.45 (m, 2H), 8.22 (br. s., 1H), 7.12-7.45 (m, 8H). HRMS (ESI)calcd for C₁₈H₁₃BrN₄O₂S₂ [M+H]⁺ 460.9736, found 460.9728.

N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0;R7′=4-trifluoromethoxyphenyl]

HPLC (254 nm): R_(t): 4.84 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.28 (br. s., 1H), 10.49 (br. s., 1H),8.39-8.43 (m, 2H), 8.20 (br. s., 1H), 7.81-7.85 (m, 2H), 7.51-7.57 (m,2H), 7.05-7.39 (m, 6H). HRMS (ESI) calcd for C₂₁H₁₅F₃N₄O₃S [M+H]⁺461.089, found 461.0881.

3,5-Difluoro-N-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=3,5-difluoro-phenyl]

HPLC (254 nm): R_(t): 5.25 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.30 (br. s., 1H), 10.58 (br. s., 1H),8.38-8.43 (m, 2H), 8.21 (br. s., 1H), 7.55-7.65 (m, 1H), 7.35-7.42 (m,3H), 7.26-7.33 (m, 1H), 7.07-7.20 (m, 4H). HRMS (ESI) calcd forC₂₀H₁₄F₂N₄O₂S [M+H]⁺ 413.0879, found 413.0870.

2,5-Difluoro-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide(Cmpd. 2)

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=2,5-difluoro-phenyl]

HPLC (254 nm): R_(t): 5.06 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.29 (br. s., 1H), 10.83 (br. s., 1H),8.38-8.44 (m, 2H), 8.21 (br. s., 1H), 7.45-7.61 (m, 3H), 7.06-7.40 (m,6H). HRMS (ESI) calcd for C₂₀H₁₄F₂N₄O₂S [M+H]⁺ 413.0879, found 413.0864.

Pyridine-3-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=pyridin-3-yl]

HPLC (254 nm): R_(t): 4.28 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.29 (br. s., 1H), 10.57 (br. s., 1H),8.85 (d, J=2.0 Hz, 1H), 8.79 (dd, J=1.5, 4.8 Hz, 1H), 8.42 (d, J=3.7 Hz,2H), 8.21 (br. s., 1H), 8.05-8.10 (m, 1H), 7.60 (dd, J=5.1, 7.6 Hz, 1H),7.07-7.40 (m, 6H). HRMS (ESI) calcd for C₁₉H₁₅N₅O₂S [M+H]⁺ 378.1019,found 378.1010.

2-Methyl-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=2-methyl-phenyl]

HPLC (254 nm): R_(t): 5.07 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.26 (br. s., 1H), 10.47 (br. s., 1H),8.41 (d, J=5.9 Hz, 2H), 8.19 (br. s., 1H), 7.75 (s, 1H), 7.43-7.53 (m,1H), 6.98-7.40 (m, 8H), 2.55 (s, 3H). HRMS (ESI) calcd for C21H18N4O₂S[M+H]⁺ 391.1223, found 391.1221.

4-Pyrazol-1-yl-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-pyrazol-1-yl-phenyl]

HPLC (254 nm): R_(t): 5.03 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.27 (br. s., 1H), 10.39 (br. s., 1H),8.58 (d, J=2.4 Hz, 1H), 8.37 (br. s., 2H), 7.89-8.25 (m, 4H), 7.77-7.83(m, 2H), 6.90-7.35 (m, 6H), 6.60 (dd, J=1.7, 2.6 Hz, 1H). HRMS (ESI)calcd for C₂₃H₁₈N₆O₂S [M+H]⁺ 443.1285, found 443.1270.

4-Chloro-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-chloro-phenyl]

HPLC (254 nm): R_(t): 5.31 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.28 (br. s., 1H), 10.44 (br. s., 1H),8.42 (d, J=5.6 Hz, 2H), 8.20 (br. s., 1H), 7.68-7.74 (m, 2H), 7.58-7.66(m, 2H), 7.05-7.40 (m, 6H). HRMS (ESI) calcd for C₂₀H₁₆ClN₄O₂S [M+H]⁺411.0677, found 411.0691.

3,4-Dichloro-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=3,4-dichloro-phenyl]

HPLC (254 nm): R_(t): 5.68 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.30 (br. s., 1H), 10.52 (br. s., 1H),8.40-8.44 (m, 2H), 8.21 (br. s., 1H), 7.82-7.90 (m, 2H), 7.61-7.68 (m,1H), 7.08-7.44 (m, 6H). HRMS (ESI) calcd for C₂₀H₁₄Cl₂N₄O₂S [M+H]⁺445.0288, found 445.0293.

N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0;R7′=3-trifluoromethyl-phenyl]

HPLC (254 nm): R_(t): 5.54 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.21 (br. s., 1H), 10.51 (br. s., 1H),8.86 (br. s., 2H), 7.60-7.99 (m, 5H), 6.68-7.22 (m, 6H). HRMS (ESI)calcd for C₂₁H₁₅F₃N₄O₂S [M+H]⁺ 445.0941, found 445.0958.

N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0;R7′=4-trifluoromethyl-phenyl]

HPLC (254 nm): R_(t): 5.60 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.40 (br. s., 1H), 10.62 (br. s., 1H),8.49 (d, J=6.3 Hz, 2H), 8.27 (br. s., 1H), 7.88-8.01 (m, 4H), 7.30 (d,J=6.0 Hz, 2H), 7.07-7.25 (m, 4H). HRMS (ESI) calcd for C₂₁H₁₆F₃N₄O₂S[M+H]⁺ 445.0941, found 445.0949.

2-Methoxy-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=2-methoxy-phenyl]

HPLC (254 nm): R_(t): 4.81 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.26 (br. s., 1H), 10.05 (br. s, 1H), 8.39(d, J=5.6 Hz, 2H), 8.21 (br. s., 1H), 7.67 (dd, J=1.6, 7.8 Hz, 1H), 7.57(t, J=8.4 Hz, 1H), 7.05-7.37 (m, 7H), 7.01 (t, J=7.7 Hz, 1H), 3.82 (s,3H). HRMS (ESI) calcd for C₂₁H₁₈N₄O₃S [M+H]⁺ 407.1173, found 407.1176.

Furan-2-sulfonic acid [3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]amide(Cmpd. 6)

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=2-furyl]

HPLC (254 nm): R_(t): 4.58 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.34 (br. s., 1H), 10.70 (br. s., 1H),8.42-8.52 (m, 2H), 8.26 (br. s., 1H), 7.94 (dd, J=0.9, 1.8 Hz, 1H),6.95-7.45 (m, 7H), 6.62 (dd, J=1.7, 3.5 Hz, 1H). HRMS (ESI) calcd forC₁₈H₁₄N₄O₃S

[M+H]⁺ 367.0860, found 367.0870.

Benzo[b]thiophene-3-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]amide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=benzo[b]thiophen-3-yl]

HPLC (254 nm): R_(t): 5.34 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.21 (br. s., 1H), 10.69 (br. s., 1H),8.35 (br. s., 2H), 7.86-8.26 (m, 3H), 6.80-7.52 (m, 9H). HRMS (ESI)calcd for C₂₂H₁₆N₄O₂S₂ [M+H]⁺ 433.0788, found 433.0788.

Thiophene-3-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide (Cmpd. 7)

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=3-thiophen-3-yl]

HPLC (254 nm): R_(t): 4.71 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.28 (br. s., 1H), 10.27 (br. s., 1H),8.43 (dd, J=1.3, 4.6 Hz, 2H), 7.91-8.24 (m, 2H), 7.71 (dd, J=3.0, 5.2Hz, 1H), 7.05-7.40 (m, 7H). HRMS (ESI) calcd for C₁₈H₁₄N₄O₂S₂ [M+H]⁺383.0631, found 383.0648.

Benzothiazole-6-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=benzothiazol-6-yl]

HPLC (254 nm): R_(t): 4.63 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.26 (br. s., 1H), 10.46 (br. s., 1H),9.61 (s, 1H), 8.64 (br. s., 1H), 8.33 (br. s., 2H), 8.23 (d, J=8.7 Hz,1H), 8.19 (s, 1H), 7.84 (dd, J=2.0, 8.7 Hz, 1H), 7.00-7.41 (m, 6H). HRMS(ESI) calcd for C₂₁H₁₅N₅O₂S₂ [M+H]⁺ 434.0740, found 434.0755.

N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-methanesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=methyl]

HPLC (254 nm): R_(t): 3.14 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.39 (br. s., 1H), 9.82 (br. s., 1H), 8.51(d, J=5.4 Hz, 2H), 7.39 (d, J=5.2 Hz, 2H), 7.24 (m, 2H), 7.11 (m, 2H),6.98 (m, 2H). HRMS (ESI) calcd for C15H14N4O₂S [M+H]+ 315.091, found315.0916.

N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=phenyl]

HPLC (254 nm): R_(t): 4.02 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.27 (br. s., 1H), 10.35 (br. s., 1H), 8.40(d, J=5.9 Hz, 2H), 8.19 (br. s., 1H), 7.68-7.72 (m, 2H), 7.60 (t, J=7.2Hz, 1H), 7.52 (t, J=7.7 Hz, 2H), 7.26 (br. s., 1H), 7.13 (d, J=6.1 Hz,2H), 7.04 (d, J=7.2 Hz, 1H). HRMS (ESI) calcd for C20H16N4O₂S [M+H]+377.1067, found 377.1075

N-{4-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenylsulfamoyl]-phenyl}-acetamide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-acetylamino-phenyl]

HPLC (254 nm): R_(t): 3.54 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.29 (br. s., 1H), 10.28 (s, 1H), 8.38-8.41(m, 2H), 8.31 (s, 1H), 8.11 (br. s., 1H), 7.67-7.71 (m, 2H), 7.61-7.64(m, 2H), 7.26 (t, J=7.0 Hz, 1H), 7.11-7.14 (m, 2H), 7.03 (d, J=7.6 Hz,1H), 2.05 (s, 3H). HRMS (ESI) calcd for C22H19N5O₃S [M+H]+ 434.1282,found 434.1295

Thiophene-2-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=thiophen-2-yl]

HPLC (254 nm): R_(t): 3.93 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.28 (br. s., 1H), 8.41 (d, J=5.7 Hz, 2H),8.05-8.33 (m, 1H), 7.83 (br. s., 1H), 7.42 (br. s., 1H), 7.22-7.35 (m,1H), 7.17 (d, J=5.2 Hz, 3H), 6.91-7.12 (m, 2H). HRMS (ESI) calcd forC18H14N4O2S2 [M+H]+ 383.0631, found 383.0633.

4-Methyl-isoxazole-5-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-methyl-isoxazole-5-yl]

HPLC (254 nm): R_(t): 3.93 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.44 (br. s., 1H), 7.30 (br. s., 1H),7.12-7.25 (m, 2H), 7.07 (s, 1H), 6.86-7.04 (m, 1H), 1.93 (d, J=6.2 Hz,1H), 1.76 (s, 3H). HRMS (ESI) calcd for C18H15N5O3S [M+H]+ 382.0969,found 382.0976.

3-Methyl-3H-imidazole-4-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0;R7′=3-methyl-3H-imidazole-4-yl]

HPLC (254 nm): R_(t): 3.00 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.26 (br. s., 1H), 10.25 (br. s., 1H),8.34-8.47 (m, 2H), 7.72 (s, 2H), 7.09-7.39 (m, 4H), 7.01 (br. s., 1H),3.63 (s, 3H). HRMS (ESI) calcd for C18H16N6O2S [M+H]+ 381.1128, found381.1143.

3H-Imidazole-4-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=3H-imidazole-4-yl]

HPLC (254 nm): R_(t): 3.76 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.25 (s, 1H), 10.12 (s, 1H), 8.38 (dd,J=1.5, 4.6 Hz, 2H), 8.07 (br. s., 1H), 7.74 (d, J=1.1 Hz, 1H), 7.63 (s,1H), 7.17-7.29 (m, 3H), 7.10-7.16 (m, 2H), 6.95 (d, J=7.2 Hz, 1H). HRMS(ESI) calcd for C17H14N6O2S [M+H]+ 367.0972, found 367.0965.

1H-Pyrazole-4-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)C, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=pyrazol-4-yl]

HPLC (254 nm): R_(t): 3.97 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.56 (br. s, 1H), 13.27 (br. s, 1H), 10.08(s, 1H), 8.39-8.45 (m, 2H), 7.70-8.20 (m, 3H), 7.20-7.40 (m, 3H),7.10-7.18 (m, 2H), 7-7.08 (m, 1H). HRMS (ESI) calcd for C17H14N6O2S[M+H]+ 367.0972, found 367.0962.

Example 3 3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-carbamic acidmethyl ester

[(I)D, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=methyl]

The above carbamate was prepared in an analogous way according toMethods G and M using a solid phase approach. The amino derivativeimmobilized on the resin obtained as described in Example 1 wasderivatized and then cleaved from the resin as described below.

Method G Step d

A solution of DIPEA (103 μL, 0.06 mmol) and the appropriatechloroformate (0.06 mmol) in 2 ml of DCM was added to a suspension ofthe resin obtained in Step a (Example 1) (100 mg, 0.01 mmol) in DCM (1ml). The obtained suspension was stirred for 20 h at rt, filtered,washed with DCM, DMF and MeOH, dried under nitrogen flux and used in thenext step.

Method M Step a

A solution of 2 ml of TFA 20% in DCM were added to 100 mg of the resinsobtained in Step c in the Quest vessels. The red suspension was stirredfor 1 h then filtered and the resin washed twice with 1 ml of DCM. Thefiltered solution was evaporated under nitrogen flux to give the productas a crude solid, which was purified by preparative HPLC.

HPLC (254 nm): R_(t): 3.25 min

¹H NMR (401 MHz, DMSO-d₆), δ=13.28 (br. s., 1H), 9.72 (s, 1H), 8.40-8.47(m, 2H), 8.11 (br. s., 1H), 7.51-7.57 (m, 2H), 7.34 (t, J=7.8 Hz, 1H),7.23-7.27 (m, 2H), 7.02 (d, J=7.7 Hz, 1H), 3.65 (s, 3H). HRMS (ESI)calcd for C₁₆H₁₄N₄O₂ [M+H]⁺ 295.1190, found 295.1184.

Operating in an analogous way the following carbamate was prepared:

[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-carbamic acid4-methoxy-phenyl ester

(I)D, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-methoxyphenyl]

HPLC (254 nm): R_(t): 5.31 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.32 (br. s., 1H), 8.86 (s., 1H), 8.47 (d,J=6.0 Hz, 2H), 7.61 (br. s., 1H), 7.30-7.36 (m, 3H), 7.10-7.16 (m, 3H),6.92-6.99 (m, 3H), 6.88 (s, 1H), 3.66 (s, 1H). HRMS (ESI) calcd forC₂₂H₁₈N₄O₃ [M+H]⁺ 387.1452, found 387.1470.

Example 4 1-Methyl-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=methyl]

The above urea was prepared according to Methods G and M using a solidphase approach, by substitution of an appropriate carbamate. The aminoderivative immobilized on the resin obtained as described in Example 1was derivatized and then cleaved from the resin as described below.

Method G Step f

The resin obtained in Step c (Example 3) (0.125 mmol, 1 eq.) wassuspended in dry DCM (2.5 ml) and methylamine (1.25 mmol, 10 eq.) wasadded. The final suspension was shaken for 24-48 h at room temperaturein a sealed reactor. The resin was rinsed with dioxane (×2), DMF (×2),DCM (×2), DMF (×2), MeOH (×2) and DCM (×2). A solution of TFA 20% in DCM(2 ml) was added to the resin in the Quest vessels. The red suspensionwas shaken for 1 h then filtered and the resin washed twice with 1 ml ofDCM. The filtered solution was evaporated under nitrogen flux to givethe products as a an oil, which was purified by preparative HPLC.

Method M Step a

A solution of TFA 20% in DCM (2 mL) was added to 100 mg of the resinsobtained in Step i in the Quest vessels. The red suspension was stirredfor 1 h then filtered and the resin washed twice with 1 ml of DCM. Thefiltered solution was evaporated under nitrogen flux to give the productas a crude solid, which was purified by preparative HPLC.

HPLC (254 nm): R_(t): 2.91 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.33 and 13.24 (2br. s., 1H, tautomers),8.62 and 8.52 (2br. s., 1H, tautomers), 8.42-8.45 (m, 2H), 8.23 and 7.95(2br. s., 1H, tautomers), 7.39-7.51 (m, 1H), 7.18-7.37 (m, 3H),6.78-7.07 (m, 1H), 5.98 (d, J=14.5 Hz, 1H), 2.62 (d, J=4.6 Hz, 3H). HRMS(ESI) calcd for C16H15N5O [M+H]+ 294.135, found 294.1346.

Operating in an analogous way the following urea was prepared:

[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=H]

HPLC (254 nm): R_(t): 2.54 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.23 (br. s., 1H), 8.61 (s, 1H), 8.42-8.45(m, 2H), 8.09 (br. s., 1H), 7.46-7.50 (m, 2H), 7.24-7.29 (m, 3H),6.89-6.96 (m, 1H), 5.84 (s, 2H). HRMS (ESI) calcd for C₁₅H₁₃N₅O [M+H]⁺280.1193, found 280.1201.

Example 5 N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-acetamide

[(I)G, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7=methyl]

The above amide was prepared according to Methods G and M using a solidphase approach, the amino derivative immobilized on the resin obtainedas described in Example 1 was derivatized and then cleaved from theresin as described below.

Method G Step h

Acetic acid (0.5 mmol, 5 eq.) was added to a solution of DIPEA (0.6mmol, 6 eq.) and PyBOP (0.5 mmol, 5 eq.) in dry DCM (2.5 ml) and thesolution was stirred for 30 min, then the mixture was added to resin(0.1 mmol, 1 eq.) and shaken at 25° C. in a reactor (Quest 210™ orMiniblocks™). The resin was rinsed with DCM (×2), DMF (×2), MeOH (×2),DMF (×2) and DCM (×2) and then dried in nitrogen flux. A solution of TFA20% in DCM (2 mL) was added to the resin in the Quest vessels. The redsuspension was shaken for 1 h then filtered and the resin washed twicewith 1 ml of DCM. The filtered solution was evaporated under nitrogenflux to give the products as an oil, which was purified by preparativeHPLC.

Method M Step a

A solution of TFA 20% in DCM (2 mL) was added to 100 mg of the resinsobtained in Step g in the Quest vessels. The red suspension was stirredfor 1 h then filtered and the resin washed twice with 1 ml of DCM. Thefiltered solution was evaporated under nitrogen flux to give the productas a crude solid, which was purified by preparative HPLC.

HPLC (254 nm): R_(t): 2.98 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.41 and 13.31 (2br. s., 1H, tautomers),10.06 and 9.97 (2br. s., 1H, tautomers), 8.46 (d, J=4.02 Hz, 2H), 8.27and 7.99 (2br. s., 1H, tautomers), 7.69 (br. s., 1H), 7.31 (br. s., 2H),7.05 (br. s., 1H), 2.03 (s, 3H). HRMS (ESI) calcd for C16H14N4O [M+H]+279.1241, found 279.1240

Operating in an analogous way the following amides were prepared:

5-Oxo-pyrrolidine-2-carboxylic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)G, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7=5-oxo-pyrrolidin-2-yl]

HPLC (254 nm): R_(t): 5.50 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.31 (br. s., 1H), 10.11 (br. s., 1H),8.42-8.44 (m, 2H), 8.30 (s, 1H), 7.86 (s, 1H), 7.25 (d, J=6.1 Hz, 2H),7.08 (br. s., 1H), 4.17 (dd, J=4.3, 8.6 Hz, 1H), 2.26-2.40 (m, 1H),2.08-2.25 (m, 2H), 1.91-2.03 (m, 1H). HRMS (ESI) calcd for C19H17N5O2[M+H]+ 348.1455, found 348.1462.

Cyclopropanecarboxylic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)G, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7=cyclopropyl]

HPLC (254 nm): R_(t): 3.43 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.36 and 13.27 (2br. s., 1H, tautomers),10.29 and 10.20 (2br. s., 1H, tautomers), 8.43 (d, J=6.1 Hz, 2H), 8.23(s, 1H), 7.68 (br. s., 1H), 7.25 (d, J=5.0 Hz, 2H), 1.76 (quin, J=6.2Hz, 1H), 0.69-0.84 (m, 4H). HRMS (ESI) calcd for C18H16N4O [M+H]+305.1397, found 305.1403.

Pyridine-2-carboxylic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)G, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7=2-pyridyl]

HPLC (254 nm): R_(t): 4.01 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.41 and 13.31 (2br. s., 1H, tautomers),10.77 and 10.68 (2br. s., 1H, tautomers), 8.74 (dt, J=0.8, 4.0 Hz, 1H),8.42-8.48 (m, 2H), 8.27 (br. s., 1H), 8.13-8.16 (m, 1H), 8.10 (br. s.,1H), 8.04-8.10 (m, 1H), 7.99 (br. s., 1H), 7.90 (br. s., 1H), 7.68 (ddd,J=1.2, 4.9, 7.4 Hz, 1H), 7.29 (d, J=3.5 Hz, 2H), 7.14 (br. s., 1H). HRMS(ESI) calcd for C20H15N5O [M+H]+ 342.135, found 342.1349

Thiophene-2-carboxylic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)G, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7=2-thiofenyl]

HPLC (254 nm): R_(t): 3.99 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.41 and 13.32 (2br. s., 1H, tautomers),10.32 and 10.28 (2br. s., 1H, tautomers), 8.45 (dd, J=1.4, 4.7 Hz, 2H),8.26 (br.s., 1H), 8.02 (d, J=3.2 Hz, 1H), 7.87 (d, J=4.9 Hz, 2H), 7.36(br. s., 1H), 7.28 (br. s., 2H), 7.23 (dd, J=3.8, 4.9 Hz, 1H), 7.09 (br.s., 1H). HRMS (ESI) calcd for C19H14N4O S [M+H]+ 347.0961, found347.0969.

N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2-ureido-acetamide

[(I)G, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7=ureidomethyl]

HPLC (254 nm): R_(t): 2.48 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.39 and 13.29 (2br. s., 1H, tautomers),9.98 (br.s., 1H), 8.37-8.52 (m, 1H), 8.24 and 7.97 (2br. s., 1H,tautomers), 7.70 (s, 1H), 7.26 (d, J=5.9 Hz, 1H), 5.67 (s, 1H), 4.08(br. s., 1H), 3.80 (d, J=5.7 Hz, 1H), 3.18 (s, 2H). HRMS (ESI) calcd forC17H16N6O2 [M+H]⁺ 337.1408, found 337.1417.

Example 61-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea(Cmpd. 1)

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H;R7=4-trifluoromethyl-phenyl]

Ureas can also be prepared in solution, according to Method G, asdescribed below.

Method G Step a 3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine

1.27 g (4.77 mmol) of 4-[3-(3-nitro-phenyl)-1H-pyrazol-4-yl]-pyridinewas suspended in methanol (200 mL). Pd/C 10% (250 mg) was added and themixture was agitated under hydrogen pressure (50 psi) in a Parrapparatus at room temperature for 4 hours. The catalyst was thenfiltered on a Celite pad and washed with methanol. The filtrate wasconcentrated to dryness to obtain 1.1 g (98% yield) of3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine as an off-white solid.

HPLC (254 nm): R_(t): 2.91 min.

¹H NMR (401 MHz, DMSO-d₆) (selected signals) δ=8.67 (d, J=6.6 Hz, 2H),8.40 (br. s., 1H), 7.77 (d, J=6.3 Hz, 2H), 7.19 (t, J=7.7 Hz, 1H), 6.76(m, 1H), 6.75 (m, 1H), 6.65 (d, J=6.6 Hz, 1H).

HRMS (ESI) calcd for C14H12N4 [M+H]+ 237.1135, found 237.1134.

Step e1-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H;R7=4-trifluoromethyl-phenyl]

To 3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (700 mg, 3 mmol) inanhydrous pyridine (15 mL) at 0° C. 4-trifluoromethylphenylisocyanate(420 μL, 3 mmol) was added. The reaction was stirred for 2 hours at 0°C. under nitrogen atmosphere to give a mixture of monourea and bis-ureaas regioisomeric mixture. Solvent was removed under reduced pressure.The residue was dissolved in methanol (15 mL) and triethylamine (1 mL,7.8 mmol) was added and the reaction was stirred at room temperatureovernight. After this time only the monourea could be detected byHPLC/MS. The solvent was removed under reduced pressure and the residuewas dissolved in ethyl acetate (100 mL) and washed successively withwater (3×50 mL). The crude was purified by silica gel columnchromatography (DCM/methanol 9:1) to give the desired product as a whitesolid (75%).

HPLC (254 nm): R_(t): 5.92 min.

¹H NMR (401 MHz, DMSO-d₆), δ=13.40 and 13.29 (2br s, 1H, tautomers),9.10 and 9.05 (2br s, 1H, tautomers), 8.93 and 8.84 (2br s, 1H,tautomers), 8.44-8.48 (m, 2H), 8.25 and 7.96 (2br s, 1H, tautomers),7.60-7.67 (m, 4H), 7.26-7.56 (m, 5H), 7.00-7.09 (m, 1H). HRMS (ESI)calcd for C₂₂H₁₆F₃N₅O [M+H]⁺ 424.1380, found 424.1367.

Operating in an analogous way the following product was prepared:

1-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-thiophen-3-yl-urea

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=thiophen-3-yl]

HPLC (254 nm): R_(t): 4.90 min.

¹H NMR (401 MHz, DMSO-d₆) (selected signals) δ=13.39 and 13.27 (2br s,1H, tautomers), 8.94 and 8.88 (2br s, 1 H, tautomers), 8.76 and 8.66(2br s, 1H, tautomers), 8.45 and 8.42 (2 m, 2H, tautomers), 7.96 and7.92 (2br s, 1H, tautomers), 7.43 (dd, J=5.12, 3.29 Hz, 1H), 7.26 (dd,J=3.29, 1.34 Hz, 1H), 7.25-7.32 (m, 2H), 7.28 (br s, 1H), 7.05 (dd,J=5.12, 1.34 Hz, 1H). HRMS (ESI) calcd for C19H15N5OS [M+H]+ 362.107,found 362.1066.

Example 71-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-thiourea

[(I)F, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-trifluoromethylphenyl]

The above compound was prepared according to Method G (Step g) asdescribed below:

To a solution of 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (31 mg,0.131 mmol) (prepared as described in Example 6) in adichloromethane/acetone (1:1,5 mL)(4-trifluoromethyl-phenyl)-thioisocyanate (32 mg, 0.157 mmol) was added.The mixture was stirred at room temperature overnight and thenevaporated to dryness. The residue taken up with methanol (5 mL), TEA (2mL) was added, and the solution was stirred at room temperatureovernight. After evaporation to dryness the compound was purified byflash chromatography, over silica gel, using dichloromethane-methanol(98:2) as the eluant system.1-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-thioureawas obtained as a colorless solid (15 mg, 87%)

¹H NMR (401 MHz, DMSO-d₆) δ=13.41, 13.29 (ds, 1H), 10.10 (br. s., 2H),8.43 (d, J=6.1 Hz, 2H), 8.24, 7.94 (ds, 1H), 7.76-7.73 (m, 4H),7.58-7.20 (m, 6H). HRMS (ESI) calcd for C22H17F3N5S [M+H]+ 440.1151,found 440.1146.

Example 8N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2-(4-trifluoromethyl-phenyl)-acetamide(Cmpd. 16) [(I)G, X═CH; R1, R2, R3, R4, R5, R6=H; m=0;R7=4-trifluoromethylphen-1-ylmethyl]

Method G Step h

To a suspension of 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (80mg, 0.339 mmol) (prepared as described in Example 6) in dichloromethane(8 mL), were added in the following order:(4-trifluoromethyl-phenyl)-acetic acid (138 mg, 0.678 mmol), DIPEA (131mg, 174 uL, 1.017 mol) and TBTU (326 mg, 1.017 mol). The reactionmixture was stirred at room temperature for 4 hours. Then it was pouredinto a solution of saturated NaHCO₃, the phases separated, and theorganic phase was washed twice with saturated NaHCO₃, and twice withwater. The organic solvent was evaporated, and the residue taken up withmethanol (5 mL). TEA (2 mL) was added, and the solution was stirred atroom temperature overnight. After evaporation to dryness the compoundwas purified by flash chromatography, over silica gel, usingdichloromethane-methanol (97:3) as the eluant system.N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2-(4-trifluoromethyl-phenyl)-acetamidewas obtained as a colorless solid (125 mg, 87%).

¹H NMR (401 MHz, DMSO-d₆) δ=13.37, 13.27 (ds, 1H), 10.36, 10.27 (ds,1H), 8.43 (d, J=5.9 Hz, 2H), 8.23, 7.94 (ds, 1H), 7.72-7.02 (m, 8H),3.76 (s, 2H). HRMS (ESI) calcd for C23H17F3N4O [M+H]+ 423.1427, found423.1427.

Operating in analogous way the following compounds were prepared:

1-(4-Trifluoromethyl-phenyl)-cyclopropanecarboxylic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)G, X═CH; R1, R2, R3, R4, R5, R6=H; m=0;R7=1-(4-trifluoromethylphenyl)-cycloprop-1-yl]

¹H-NMR (401 MHz, DMSO-d₆) δ=13.25 (s, 1H), 9.5 (s, 1H), 8.42 (dd, J=1.4,4.7 Hz, 2H), 8.23 (s, 1H), 7.65-7.70 (m, 4H), 7.52-7.58 (m, 4H),7.20-7.26 (m, 2H), 1.46-1.53 (m, 2H), 1.15-1.22 (m, 2H).

N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2-(4-trifluoromethyl-phenyl)-propionamide

[(I)G, X═CH; R1, R2, R3, R4, R5, R6=H; m=0;R7=1-(4-trifluoromethylphenyl)-ethyl]

HPLC (254 nm): R_(t): 6.07 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.27 (s, 1H), 10.18 (s, 1H), 8.39-8.45 (m,2H), 8.22 (s, 1H), 7.53-7.79 (m, 6H), 7.27-7.46 (m, 1H), 7.20-7.26 (m,2H), 6.90-7.12 (m, 1H), 3.94 (q, J=7.1 Hz, 1H), 1.43 (d, J=7.0 Hz, 3H).

HRMS (ESI) calcd for [M+H]+ 437.1584, found 4370.5588

Example 91-(4-Chloro-3-trifluoromethyl-phenyl)-3-{3-[1-(2-fluoro-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-urea(Cmpd. 5) [(I)E, X═CH; R2, R3, R4, R5, R6=H; m=2, R1=F; Y═H;R7=4-chloro-3-trifluoromethyl-1-phenyl]

Method A Step h4-[1-(2-fluoroethyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine

To 4-[3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine (100 mg, 0.37 mmol) inN,N-dimethylformamide (3.7 mL) 1-iodo-2-fluoroethane (128 mg, 0.75 mmol)and cesium carbonate (240 mg, 0.74 mmol) were added. The mixture wasstirred at 50° C. for 3 hours to give the alkylated product as a 5:1regiosomeric mixture (at 254 nm). Solvent was removed under reducedpressure and the residue was dissolved in ethyl acetate (100 mL) andwashed successively with saturated NaHCO₃ solution (3×50 mL), and brine(1×50 mL). The organic solution was dried over Na₂SO₄ and filtered, andthe solvent was evaporated under reduced pressure. The major regioisomerwas isolated by reverse phase column chromatography in 72% yield.

Method G Step a3-[1-(2-fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl]aniline

To 4-[1-(2-fluoroethyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine in asolution of dioxane/water (5:1) ammonium chloride (144 mg, 2.7 mmol) andzinc (70 mg, 1.08 mmol) were added. The reaction was stirred at 80° C.After two hours the reaction was allowed to cool to room temperature andit was poured into Na₂HPO₄ (pH=8) solution and extracted with ethylacetate. The organic layer was washed with brine (1×50 mL), dried overNa₂SO₄ and filtered. The filtrate was concentrated under reducedpressure and it was used in the next step without further purification.

Step e1-(4-Chloro-3-trifluoromethyl-phenyl)-3-{3-[1-(2-fluoro-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-urea

[(I)E, X═CH; R2, R3, R4, R5, R6=H; m=2; R1=F; Y═H;R7=4-chloro-3-trifluoromethyl-1-phenyl]

To 3-[1-(2-fluoroethyl)-4-(pyridin-4-yl)-1H-pyrazol-3-yl]aniline (80 mg,0.28 mmol) in anhydrous methylene chloride (1.5 mL)4-chloro-3-(trifluoromethyl)phenyl isocyanate (81.5 mg, 0.37 mmol) wasadded. The reaction was stirred at room temperature under nitrogenatmosphere for two hours. The solvent was removed under reduced pressureand the crude was purified by silica gel column chromatography (7:3ethyl acetate/hexane, grading to 100% acetate) to give the desiredproduct as white solid in 64% yield over two steps.

HPLC (254 nm): R_(t): 6.66 min.

¹H NMR (401 MHz, DMSO-d₆) δ=9.10 (s, 1H), 8.91 (s, 1H), 8.48 (d, J=5.9Hz, 2H), 8.28 (s, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.61-7.63 (m, 2H), 7.58(t, J=1.8 Hz, 1H), 7.46-7.54 (m, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.23-7.28(m, 2H), 7.01 (dt, J=1.3, 7.6 Hz, 1H), 4.75-4.99 (m, 2H), 4.32-4.61 (m,2H). HRMS (ESI) calcd for C24H18ClF4N5O [M+H]+ 504.1209, found 504.1195.

Operating in an analogous way the following compounds were prepared:

1-(4-Chloro-3-trifluoromethyl-phenyl)-3-{3-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenyl}-urea

[(I)E, X═CH; R2, R3, R4, R5, R6=H; m=1; R1=CF₃; Y═H;R7=4-chloro-3-trifluoromethyl-1-phenyl]

HPLC (254 nm): R_(t): 7.06 min.

¹H NMR (401 MHz, DMSO-d₆) δ=9.11 (s, 1H), 8.94 (s, 1H), 8.48-8.56 (m,2H), 8.35 (s, 1H), 8.09 (d, J=1.7 Hz, 1H), 7.58-7.64 (m, 3H), 7.48-7.55(m, 1H), 7.32 (t, J=7.9 Hz, 1H), 7.26-7.29 (m, 2H), 6.99 (ddd, J=1.0,1.3, 7.9 Hz, 1H), 5.18-5.32 (m, 2H). HRMS (ESI) calcd for C24H16ClF6N5O[M+H]+ 540.1021, found 540.101.

1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[3-(1-cyclobutyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R2, R3, R4, R5, R6=H; m=0; R1=cyclobutyl; Y═H;R7=4-chloro-3-trifluoromethyl-1-phenyl]

HPLC (254 nm): R_(t): 7.31 min.

¹H NMR (401 MHz, DMSO-d₆) δ=9.10 (s, 1H), 8.92 (s, 1H), 8.46 (d, J=6.0Hz, 2H), 8.34 (s, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.59-7.64 (m, 2H),7.51-7.56 (m, 2H), 7.31 (t, J=7.9 Hz, 1H), 7.24-7.28 (m, 2H), 7.01 (dt,J=1.2, 7.7 Hz, 1H), 4.91 (quin, J=8.4 Hz, 1H), 2.55-2.63 (m, 2H),2.38-2.49 (m, 2H), 1.77-1.90 (m, 2H). HRMS (ESI) calcd for C26H21ClF3N5O[M+H]+ 512.146, found 512.1453.

1-[3-(1-But-3-enyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-chloro-3-trifluoromethyl-phenyl)-urea

[(I)E, X═CH; R2, R3, R4, R5, R6=H; m=2; R1=vinyl; Y═H;R7=4-chloro-3-trifluoromethyl-phenyl]

HPLC (254 nm): R_(t): 7.14 min.

¹H NMR (401 MHz, DMSO-d₆) δ=9.10 (s, 1H), 8.90 (s, 1H), 8.51 (br. s.,2H), 8.25 (s, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.59-7.67 (m, 2H), 7.56 (t,J=1.7 Hz, 1H), 7.47-7.53 (m, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.27 (br. s.,2H), 6.99-7.02 (m, 1H), 5.79-5.93 (m, J=17.1, 10.3, 6.7, 6.7 Hz, 1H),5.11-5.19 (m, J=17.3, 1.7, 1.7, 1.5 Hz, 1H), 5.05-5.10 (m, 1H), 4.26 (t,J=7.1 Hz, 2H), 2.60-2.71 (m, 2H). HRMS (ESI) calcd for C26H21ClF3N5O[M+H]+ 512.146, found 512.1453.

Example 101-[3-(1-Isobutyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea(Cmpd. 50)

[(I)E, X═CH; R2, R3, R4, R5, R6=H; m=1; R1=i-propyl; Y═H;R7=4-trifluoromethyl-phenyl]

To1-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea(prepared as described in Example 6) (100 mg, 0.24 mmol) inN,N-dimethylformamide (1 mL) were added 1-iodo-2-methyl-propane (544,0.47 mmol) and cesium carbonate (152 mg, 0.47 mmol). The reaction wasstirred at 50° C. for three hours then poured into water and extractedwith ethyl acetate (50 mL). The organic layer was washed with brine,dried over anhydrous sodium sulphate, filtered and concentrated. The tworegioisomers of the pyrazole were isolated by silica gel columnchromatography (DCM/ethanol 98:2).

HPLC (254 nm): R_(t): 6.14 min.

¹H NMR (401 MHz, DMSO-d₆) δ=9.03 (s, 1H), 8.85 (s, 1H), 8.46 (d, J=6.1Hz, 2H), 8.22 (s, 1H), 7.59-7.67 (m, 4H), 7.56 (t, J=1.8 Hz, 1H),7.45-7.55 (m, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.25 (d, J=6.1 Hz, 2H), 6.99(ddd, J=1.0, 1.5, 7.6 Hz, 1H), 3.99 (d, J=7.1 Hz, 2H), 2.20 (spt, J=6.8Hz, 1H), 0.92 (d, J=6.7 Hz, 6H). HRMS (ESI) calcd for C26H24F3N5O [M+H]+480.2006, found 480.2007.

Operating in an analogous way the following compounds were prepared:

1-[3-(1-Ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea(Cmpd. n^(o) 10)

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=2; Y═H;R7=4-trifluoromethyl-phenyl]

HPLC (254 nm): R_(t): 5.56 min.

¹H NMR (401 MHz, DMSO-d₆) δ=9.03 (s, 1H), 8.85 (s, 1H), 8.46 (d, J=6.2Hz, 2H), 8.24 (s, 1H), 7.59-7.68 (m, 4H), 7.56 (t, J=1.8 Hz, 1H),7.49-7.51 (m, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.24 (d, J=6.1 Hz, 2H), 6.99(ddd, J=1.0, 1.5, 7.6 Hz, 1H), 4.22 (q, J=7.3 Hz, 2H), 1.47 (t, J=7.3Hz, 3H). HRMS (ESI) calcd for C24H20F3N5O [M+H]⁺ 452.1693, found452.1704.

1-[3-(1-Butyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea(Cmpd. n^(o) 49)

[(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=4; Y═H;R7=4-trifluoromethyl-phenyl]

HPLC (254 nm): R_(t): 5.56 min.

¹H NMR (401 MHz, DMSO-d₆) δ=9.03 (s, 1H), 8.85 (s, 1H), 8.45 (d, J=6.1Hz, 2H), 8.23 (s, 1H), 7.59-7.67 (m, 4H), 7.55 (t, J=1.8 Hz, 1H),7.47-7.51 (m, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.24 (d, J=6.1 Hz, 2H), 6.99(dt, J=1.2, 7.8 Hz, 1H), 4.18 (t, J=7.1 Hz, 2H), 1.85 (quin, J=7.3 Hz,2H), 1.34 (dq, J=7.4, 14.9 Hz, 2H), 0.93 (t, J=7.4 Hz, 3H). HRMS (ESI)calcd for C26H24F3N5O [M+H]+ 480.2006, found 480.199.

1-[3-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea(Cmpd. 48) [(I)E, X═CH; R1, R2, R3, R4, R5, R6=H; m=1; Y═H;R7=4-trifluoromethyl-phenyl]

HPLC (254 nm): R_(t): 5.15 min.

¹H NMR (401 MHz, DMSO-d₆) δ=9.04 (s, 1H), 8.85 (s, 1H), 8.46 (d, J=6.1Hz, 2H), 8.18 (s, 1H), 7.59-7.67 (m, 4H), 7.56 (t, J=1.8 Hz, 1H),7.45-7.48 (m, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.23 (d, J=6.1 Hz, 2H), 6.99(dt, J=1.2, 7.7 Hz, 1H), 3.90-3.96 (m, 3H). HRMS (ESI) calcd forC23H18F3N₅O [M+H]⁺ 438.1536, found 438.155.

1-[3-(1-Cyanomethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea(Cmpd. n^(o) 11)

[(I)E, X═CH; R2, R3, R4, R5, R6=H; m=1; R1=cyano; Y═H;R7=4-trifluoromethyl-phenyl]

HPLC (254 nm): R_(t): 6.3 min.

¹H NMR (401 MHz, DMSO-d₆) δ=9.16 (s, 1H), 9.01 (s, 1H), 8.46-8.52 (m,2H), 8.32 (s, 1H), 7.59-7.69 (m, 4H), 7.60-7.65 (m, 1H), 7.50-7.54 (m,1H), 7.32 (t, J=7.9 Hz, 1H), 7.24-7.29 (m, 2H), 7.00-6.95 (m, 1H), 5.61(s, 2H). HRMS (ESI) calcd for C24H17F3N5O [M+H]+ 463.1489, found463.1497.

2-(4-Pyridin-4-yl-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazol-1-yl)-acetamide

[(I)E, X═CH; R2, R3, R4, R5, R6=H; m=0; R1=aminocarbonylmethyl; Y═H;R7=4-trifluoromethyl-phenyl]

HPLC (254 nm): R_(t): 5.58 min.

¹H NMR (401 MHz, DMSO-d₆) δ=9.04 (s, 1H), 8.87 (s, 1H), 8.35-8.54 (m,2H), 8.19 (s, 1H), 7.59-7.68 (m, 4H), 7.58 (t, J=1.8 Hz, 1H), 7.48-7.51(m, 1H), 7.33 (s, 2H), 7.30 (t, J=7.9 Hz, 1H), 7.22-7.27 (m, 2H), 6.99(dt, J=1.2, 7.7 Hz, 1H), 4.85 (s, 2H). HRMS (ESI) calcd for C24H19F3N6O2[M+H]+ 481.1595, found 481.1596.

Example 111-{3-[1-(2-Hydroxy-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-3-(4-trifluoromethyl-phenyl)-urea(Cmpd. 14) [(I)E, X═CH; R2, R3, R4, R5, R6=H; m=2; R1=hydroxy; Y═H;R7=4-trifluoromethyl-phenyl]

The above compound was prepared as described in Example 10 using2-(2-bromo-ethoxy)-tetrahydro-pyran as alkylating agent. The protectivegroup was then removed as described below.

To1-(3-{4-pyridin-4-yl-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-phenyl)-3-(4-trifluoromethyl-phenyl)-urea(50 mg, 0.09 mmol) in methylene chloride (1 mL) p-toluenesulfonic acid(PTSA) (25.8 mg, 0.13 mmol) was added, the reaction was stirred at roomtemperature for two days. The solvent was removed under reduced pressureand the product was isolated by silica gel column chromatography(DCM/methanol 93:7).

HPLC (254 nm): R_(t): 5.8 min.

¹H NMR (401 MHz, DMSO-d₆) δ=9.09 (s, 1H), 8.92 (s, 1H), 8.55 (d, J=5.6Hz, 2H), 8.34 (s, 1H), 7.59-7.68 (m, 5H), 7.49 (m, 1H), 7.33 (t, J=7.9Hz, 1H), 7.11 (m, 2H), 7.03 (m, 1H), 5.02 (s, 1H), 4.25 (t, J=5.5 Hz,2H), 3.85 (t, J=5.4 Hz, 2H). HRMS (ESI) calcd for C24H20F3N5O2 [M+H]+468.1642, found 468.1624.

Example 12(4-Pyridin-4-yl-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazol-1-yl)-aceticacid

[(I)E, X═CH; R2, R3, R4, R5, R6=H; m=1; R1=carboxyl; Y═H;R7=4-trifluoromethyl-phenyl]

The above compound was prepared as described in Example 10 usingbromoacetic acid ethyl ester as alkylating agent. The ester was thenhydrolized as described below.

To(4-pyridin-4-yl-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazol-1-yl)-aceticacid ethyl ester in tetrahydrofuran (2 mL) and water (0.5 mL) lithiumhydroxide (7.2 mg, 0.17 mmol) was added and the reaction was stirred atroom temperature overnight. Ethyl acetate (50 mL) and 5% potassiumhydrogen carbonate solution (20 mL) were then added. The organic layerwas washed with brine, dried over anhydrous sodium sulphate, filteredand concentrated to yield the desired product.

HPLC (254 nm): R_(t): 6.38 min.

1H NMR (401 MHz, DMSO-d₆) δ=9.24 (s, 1H), 9.07 (s, 1H), 8.57 (dd, J=1.3,5.0 Hz, 2H), 8.36 (s, 1H), 7.58-7.68 (m, 5H), 7.48-7.53 (m, 1H),7.42-7.46 (m, 2H), 7.33 (t, J=7.9 Hz, 1H), 6.99-7.04 (m, 1H), 5.09 (s,2H). HRMS (ESI) calcd for C24H18F3N5O3 [M+H]⁺ 482.1435, found 482.1445.

Example 131-[3-(1-Piperidin-4-yl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea(Cmpd. 15)

[(I)E, X═CH; R2, R3, R4, R5, R6=H; m=0; R1=piperidin-4-yl; Y═H;R7=4-trifluoromethyl-phenyl]

Method A Step h4-[3-(3-Nitro-phenyl)-4-pyridin-4-yl-pyrazol-1-yl]-piperidine-1-carboxylicacid tert-butyl ester

To a suspension of 4-[3-(3-nitro-phenyl)-1H-pyrazol-4-yl]-pyridine (200mg, 0.750 mmol) in anhydrous tetrahydrofuran (3 mL) at 0° C.triphenylphosphine (293 mg, 1.12 mmol, 1.5 eq),4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.750mmol, 1 eq) and DEAD (176 μL, 1.12 mmol, 1.5 eq) were added. Thereaction was allowed to warm to room temperature and stirred undernitrogen atmosphere overnight. The regioisomeric ratio was 1:4 at 254 nmin favor of the N¹-alkylated product. The solvent was removed underreduced pressure and the residue was purified by silica gel columnchromatography (DCM/ethanol 97:3) to give 950 mg of major regioisomercontaminated with triphenylphosphinoxide.

Method G Step a Synthesis of4-[3-(3-Amino-phenyl)-4-pyridin-4-yl-pyrazol-1-yl]-piperidine-1-carboxylicacid tert-butyl ester

To crude4-[3-(3-nitro-phenyl)-4-pyridin-4-yl-pyrazol-1-yl]-piperidine-1-carboxylicacid tert-butyl ester (0.75 mmol) in methanol (20 mL) Pd/C 10% (190 mg)was added. The reaction was stirred under hydrogen atmosphere (45 psi)at room temperature for six hours. The suspension was filtered to removethe catalyst, and then concentrated to give the crude product that wasused in the next step without further purification.

Step e1-[3-(1-piperidin-4-yl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea

To4-[3-(3-amino-phenyl)-4-pyridin-4-yl-pyrazol-1-yl]-piperidine-1-carboxylicacid tert-butyl ester (0.75 mmol) in anhydrous N,N-dimethylformamide (5mL) 4-trifluoromethylphenylisocyanate (104 4, 0.75 mmol) was added at 0°C. The reaction was allowed to warm to room temperature and it wasstirred under nitrogen atmosphere overnight. The crude product waspurified by silica gel column chromatography (DCM/methanol 93:7) to give4-(4-pyridin-4-yl-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazol-1-yl)-piperidine-1-carboxylicacid tert-butyl ester.

To4-(4-pyridin-4-yl-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazol-1-yl)-piperidine-1-carboxylicacid tert-butyl ester (100 mg, 0.16 mmol) in dioxane (2 mL) HCl 4M indioxane (1 mL, 3.30 mmol) was added. After one hour the reaction wasdiluted with ethyl acetate (50 mL) and washed with saturated NaHCO₃solution (3×50 mL) and brine (1×50 mL). The organic phase was dried overNa₂SO₄, filtered and the solvent was evaporated under reduced pressure.The deprotected urea was isolated by reverse phase chromatography.

HPLC (254 nm): R_(t): 5.08 min.

¹H NMR (401 MHz, DMSO-d₆) δ=10.08 (s, 1H), 9.85 (s, 1H), 8.45 (d, J=5.7Hz, 2H), 8.30 (br. s., 2H), 8.28 (s, 1H), 7.64-7.71 (m, 3H), 7.60 (d,J=8.9 Hz, 2H), 7.50-7.55 (m, 1H), 7.22-7.31 (m, 3H), 6.90-6.95 (m, 1H),4.35-4.42 (m, 1H), 2.73-2.86 (m, 2H), 2.08-2.21 (m, 2H), 1.94-2.05 (m,2H). HRMS (ESI) calcd for C27H26F3N5O [M+H]+ 507.2115, found 507.2108.

Operating in an analogous way the following compounds were prepared:

1-{3-[1-(2-Fluoro-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-3-(4-trifluoromethyl-phenyl)-urea(Cmpd. 13)

[(I)E, X═CH; R2, R3, R4, R5, R6=H; m=2; R1=F; Y═H;R7=4-trifluoromethyl-phenyl]

HPLC (254 nm): R_(t): 6.38 min.

¹H NMR (401 MHz, DMSO-d₆) δ=9.04 (s, 1H), 8.87 (s, 1H), 8.48 (d, J=6.1Hz, 2H), 8.29 (s, 1H), 7.60-7.69 (m, 4H), 7.58 (t, J=1.8 Hz, 1H),7.47-7.53 (m, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.26-7.29 (m, 2H), 7.01 (m,1H), 4.79-4.95 (m, 2H), 4.47-4.59 (m, 2H). HRMS (ESI) calcd forC24H20F4N5O [M+H]+ 470.1599, found 470.1595.

1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[3-(1-isopropyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R2, R3, R4, R5, R6=H; m=0; R1=i-propyl; Y═H;R7=4-chloro-3-trifluoromethyl-phenyl]

HPLC (254 nm): R_(t): 7.11 min.

¹H NMR (401 MHz, DMSO-d₆) δ=9.10 (s, 1H), 8.92 (s, 1H), 8.47 (d, J=5.6Hz, 2H), 8.31 (s, 1H), 8.09 (d, J=2.1 Hz, 1H), 7.58-7.66 (m, 2H),7.49-7.57 (m, 3H), 7.26-7.34 (m, 3H), 7.01 (dt, J=1.1, 7.7 Hz, 1H),4.55-4.62 (m, 1H), 1.52 (d, J=6.6 Hz, 6H)HRMS (ESI) calcd forC₂₅H₂₂ClF₃N₅O [M+H]⁺ 500.1460, found 500.1465.

Example 141-(4-Chloro-3-trifluoromethyl-phenyl)-3-[3-(1-phenyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

[(I)E, X═CH; R2, R3, R4, R5, R6=H; m=0; R1=phenyl; Y═H;R7=4-chloro-3-trifluoromethyl-phenyl]

Method A Step g 4-[3-(3-nitro-phenyl)-1-phenyl-1H-pyrazol-4-yl]-pyridine

3-Dimethylamino-1-(3-nitro-phenyl)-2-pyridin-4-yl-propenone (150 mg,0.505 mmol) was dissolved in dry THF (2 mL) under nitrogen atmosphere.Phenylhydrazine (0.2 mL, 2.02 mmol, 4 eq) was added and the mixture washeated to 70° C. and stirred at this temperature for 1.5 hours. Themixture was concentrated to dryness. A 77:23 mixture (A % at 254 nm) oftwo regioisomers was obtained in favour of4-[5-(3-nitro-phenyl)-1-phenyl-1H-pyrazol-4-yl]-pyridine (regiochemistrydetermined at the end of the synthesis). The crude product was purifiedby reverse phase chromatography to give 100 mg (58% yield) ofphenylpyrazole still as regioisomer mixture.

Method G Step a 3-(1-phenyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine

The nitroderivative (100 mg, 0.292 mmol) was suspended in a 5:1dioxane/water mixture (2 mL). Zinc powder (77 mg, 1.18 mmol, 4 eq) wasadded, followed by ammonium chloride (157 mg, 2.94 mmol, 10 eq) and themixture was heated at 100° C. for 4 hours. The reaction mixture was thendiluted with water and ethyl acetate, pH was adjusted to 8 with NaHCO₃and the aqueous phase was extracted with ethylacetate. The organic layerwas dried over Na₂SO₄ and concentrated to dryness to obtain 65 mg (66%yield) of crude product. Regioisomeric ratio is 86:14 by HPLC (254 nm)and 2:1 by ¹H-NMR in favour of3-(2-phenyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenylamine.

Step e1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[3-(1-phenyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea

3-(1-Phenyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (asregioisomeric mixture) was dissolved in dry dichloromethane (1 mL) undernitrogen atmosphere, 4-chloro-3-trifluoromethylphenylisocyanate (61 mg,0.275 mmol, 1.4 eq) was added and the reaction mixture was stirred atroom temperature for 3 hours. The solution was concentrated to drynessand purified by chromatography on silica gel (SP1, gradientn-hexane/ethyl acetate 1:1 to pure ethyl acetate). Two pools offractions containing the two separated regioisomers were obtained,together with some mixed fractions (total yield 78%). 55 mg of1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[3-(2-phenyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ureawere obtained as colourless oil.

HPLC (254 nm): R_(t): 7.68 min.

¹H NMR (401 MHz, DMSO-d₆) δ=9.14 (s, 1H), 9.04 (s, 1H), 8.96 (s, 1H),8.55 (d, J=6.0 Hz, 2H), 8.09 (d, J=2.3 Hz, 1H), 7.96 (d, J=7.6 Hz, 2H),7.65 (m, 1H), 7.61-7.64 (m, 2H), 7.55-7.61 (m, 3H), 7.34-7.42 (m, 4H),7.12 (dt, J=1.1, 7.7 Hz, 1H).

HRMS (ESI) calcd for C28H20ClF3N5O [M+H]+534.1303, found 534.1305.

Example 154-Pyridin-4-yl-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazole-1-carboxylicacid ethyl ester (Cmpd. 47)

[(I)E, X═CH; R2, R3, R4, R5, R6=H; m=0; R1=ethoxycarbonyl; Y═H;R7=4-trifluoromethyl-phenyl]

To a suspension of1-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea(100 mg, 0.236 mmol) (prepared as described in Example 6) in THF (10 mL)DIPEA (61 mg, 81 uL, 0.427 mmol) was added. The mixture was stirred for5 minutes before adding ethyl chloroformate (31 mg, 27 uL, 0.283 mmol).After 2 hours the mixture was evaporated to dryness, taken up with ethylacetate and washed three times with water. The organic phase was driedover Na₂SO₄, evaporated to dryness and triturated with diisopropyl etherto yield4-pyridin-4-yl-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazole-1-carboxylicacid ethyl ester (90 mg, 77%).

¹H NMR (401 MHz, DMSO-d₆) δ=9.11 (s, 1H), 8.98 (s, 1H), 8.84 (s, 1H),8.50-8.57 (m, 2H), 7.61-7.68 (m, 5H), 7.56 (ddd, J=0.9, 2.2, 8.2 Hz,1H), 7.32-7.39 (m, 3H), 7.01 (ddd, J=1.0, 1.3, 7.8 Hz, 1H), 4.52 (q,J=7.2 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H). HRMS (ESI) calcd for C25H20F3N5O3[M+H]⁺ 496.1591, found 496.1587.

Preparation of -(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzonitrile

[(II)A, X═CH; R2, R3, R4, R5, R6=H; G=CN]

Method A Step a: [(3-cyano-phenyl-hydroxy-methyl]-phosphonic aciddimethyl ester

A mixture of 3-formyl-benzonitrile (10 g, 76.26 mmol), triethylamine(9.26 g, 91.05 mmol) and dimethyl-phosphite (10.91 g, 99.14 mmol) wasstirred in ethyl acetate at room temperature for 2 hours. The solventwas evaporated and the residue was dissolved in ethyl acetate (50 ml),washed with a saturated ammonium chloride solution (1×50 ml), dried(Na₂SO₄) and the filtrate was evaporated affording the crude[(3-cyanophenyl-hydroxymethyl]-phosphonic acid dimethyl ester as ayellow solid (13.60 g, 56.43 mmol, 74%).

¹H NMR (401 MHz, DMSO-d₆) δ=7.81 (q, J=1.8 Hz, 1H), 7.77 (dt, J=1.8, 7.8Hz, 2H), 7.58 (t, J=7.7 Hz, 1H), 6.51 (dd, J=5.9, 14.4 Hz, 1H), 5.16(dd, J=5.9, 13.9 Hz, 1H), 3.64 (d, J=10.2 Hz, 3H), 3.62 (d, J=10.2 Hz,3H). MS ESI (M+H) calc 242.0577; found. 242.0576 (C10H12NO4P).

Step b: [(3-cyano-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]phosphonicacid dimethyl ester

3,4-Dihydro-2H-pyran (10.83 g, 128.70 mmol) and p-toluenesulfonic acid(0.34 g, 1.75 mmol) were added to a solution of[(3-cyanophenyl-hydroxy-methyl]-phosphonic acid dimethyl ester (14.10 g,58.50 mmol) in dry toluene (195 ml) and the reaction mixture was stirredunder nitrogen atmosphere at 50° C. for 3 h. The solvent was thenremoved under vacuum and the residue was taken up with ethyl acetate(100 ml). The organic layer was washed with a saturated NaHCO₃ solution(1×100 ml), brine (1×100 ml) and dried over Na₂SO₄. The filtrate wasevaporated to dryness to give the crude[(3-cyano-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]phosphonic aciddimethyl ester as a yellow oil (19 g, 58.46 mmol, 100%).

¹H NMR (401 MHz, DMSO-d₆) δ=7.85-7.74 (m, 3H), 7.63-7.58 (m, 1H), 5.24(d, J=17.4 Hz, 1H), 5.24 (d, J=12.7 Hz, 1H), 4.96 (t, J=3.0 Hz, 1H),4.39 (t, J=2.5 Hz, 1H), 3.89 (dt, J=6.0, 11.7 Hz, 1H), 3.71 (d, J=10.5Hz, 3H), 3.64 (d, J=10.5 Hz, 3H), 3.64 (td, J=7.6, 10.4 Hz, 2H), 3.51(d, J=12.2 Hz, 1H), 1.87-1.31 (m, 6H). MS ESI (M+H) calc 326.1152;found. 326.1158 (C15H20NO5P).

Step c:3-[(E)-2-pyridin-4-yl-1-(tetrahydro-pyran-2-yloxy)-vinyl]-benzonitrile

Sodium hydride (2.28 g, 94.98 mmol) was added to a solution of[(3-cyano-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]phosphonic aciddimethyl ester (20.58 g, 63.3 mmol) in dry THF and the mixture wasstirred at room temperature for 15′. Pyridine-4-carbaldehyde (6.78 g,63.3 mmol) was then added and the reaction mixture was stirred at 50° C.for 3 h under nitrogen atmosphere. In order to affect completion afurther addition of pyridine-4-carbaldehyde (0.68 g, 6.33 mmol) wasrequired. Distilled water (40 ml) was slowly poured into the reactionmixture and the solvent (THF) was removed under reduced pressure. Thewater layer was extracted with EtOAc (3×100 ml), DCM (1×100 ml) and theorganic layers were dried over Na₂SO₄. The filtrate was evaporated todryness to give the crude product3-[(E)-2-Pyridin-4-yl-1-(tetrahydro-pyran-2-yloxy)-vinyl]-benzonitrileas a brown oil (19.0 g, 62.10 mmol, 98%).

MS ESI (M+H) calc 307.1441; found. 307.1436 (C19H18N2O2).

Step d: 3-(pyridin-4-yl-acetyl)-benzonitrile

3-[(E)-2-Pyridin-4-yl-1-(tetrahydro-pyran-2-yloxy)-vinyl]-benzonitrile(19.0 g, 62.1 mmol) was dissolved into methanol (0.4 ml) and a solutionof HCl 1N (0.04 ml) was added. The mixture was stirred at 50° C. for 1h. Upon reaction completion, the solvent was evaporated and a saturatedNaHCO₃ solution was added dropwise to the left water layer leading tothe precipitation of 3-(pyridin-4-yl-acetyl)-benzonitrile (4) as ayellow solid (9.65 g, 43.4 mmol, 70%).

¹H NMR (401 MHz, DMSO-d₆) δ=8.49-8.57 (m, 3H), 8.32 (dt, J=1.2, 8.6 Hz,1H), 8.15 (ddd, J=1.2, 1.4, 7.9 Hz, 1H), 7.79 (dd, J=0.5, 15.6 Hz, 1H),7.28-7.35 (m, 2H), 4.57 (s, 2H). MS ESI (M+H) calc 223.0866; found.223.0864 (C14H10N2O).

Step f: 3-((E)-3-dimethylamino-2-pyridin-4-yl-acryloyl)benzonitrile

3-(Pyridin-4-yl-acetyl)-benzonitrile (4.91 g, 22.1 mmol) was dissolvedinto dry toluene (0.2 ml) and dimethoxymethyl-dimethyl-amine (10.6 g,88.5 mmol) was added. The reaction mixture was stirred at 80° C. for 2 hunder nitrogen atmosphere. The solvent was removed under vacuum andcrude 3-((E)-3-Dimethylamino-2-pyridin-4-yl-acryloyl)benzonitrile wasused in the next step without further purification.

Step g: 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzonitrile

A 1 M solution of hydrazine in THF (0.090 ml, 88.5 mmol) was added to3-((E)-3-dimethylamino-2-pyridin-4-yl-acryloyl)benzonitrile (6.13 g,22.1 mmol) and the mixture was stirred at 60° C. for 1 h. The product3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzonitrile (4.89 g, 19.8 mmol, 90%)was isolated as a white solid by filtration from the reaction mixture.

HPLC (254 nm): R_(t): 3.50 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.48 (br. s., 1H), 8.49 (d, J=5.9 Hz, 2H),8.28 (d, J=1.3 Hz, 1H), 7.84-7.81 (m, 1H), 7.99-7.90 (m, 1H), 7.84 (d,J=1.1 Hz, 2H), 7.74-7.70 (m, 1H), 7.61 (t, J=8.1 Hz, 1H), 7.25 (d, J=5.9Hz, 2H). MS ESI (M+H) calc 247.0978; found. 247.0973 (C15H10N4).

Example 16 N-Benzyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=benzyl]

Method I Step a: 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzoic acidhydrochloride

A solution of 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzonitrile (1.2 g,4.87 mmol) in 3M HCl (24 ml) was heated to 150° C. for 30 minutes in amicrowave vessel. The product 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzoicacid hydrochloride was isolated as a white solid by filtration from thereaction mixture (1.03 g, 4.3 mmol, 89%).

HPLC (254 nm): R_(t): 3.18 min

¹H-NMR (401 MHz, DMSO-d₆) δ=13.13 (br.s., 1H), 8.68 (d, J=6.6 Hz, 2H),8.50 (br. s., 1H), 8.10-8.00 (m, 2H), 7.76-7.68 (m, 3H), 7.62 (t, J=8.0Hz, 1H). MS ESI (M+H) calc 266.0924; found. 266.0927 (C₁₅H₁₁N₃O₂).

Step b: N-benzyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

A solution of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride (0.029 g, 0.15 mmol, 1.5 eq) in dry DCM (1 mL) and asolution of 1-hydroxybenzotriazole (0.020 g, 0.15 mmol, 1.5 eq) andDIPEA (0.064 g, 0.50 mmol, 5 eq) in dry DMF (0.1 mL) were added to3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzoic acid hydrochloride (0.030 g,0.10 mmol, 1 eq) in dry DMF (0.200 ml). Benzylamine (2 eq) was added tothe reaction mixture, which was stirred at room temperature for 24 h.Distilled water (1.5 mL) was poured into the suspension that was stirredfor 1 h at room temperature and the organic layer was separated byfiltration through Alltech Separator Tube. The solvent was evaporatedand reverse phase purification of the crude afforded the final productas a solid.

HPLC (254 nm): R_(t): 4.88 min

¹H-NMR (401 MHz, DMSO-d₆) δ=13.3 (br.s., 1H), 9.08 (t, J=5.4 Hz, 1H),8.46 (d, J=6.0 Hz, 2H), 8.28 (d, J=0.5 Hz, 1H), 8.06-7.85 (m, 2H),7.65-7.44 (m, 2H), 7.39-7.18 (m, 7H), 4.48 (t, J=5.1 Hz, 2H). MS ESI(M+H) calc 355.1554; found. 355.1568 (C22H18N4O).

Operating in an analogous way the following amides were prepared:

3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6, R7=H; m=0; Y═H]

HPLC (254 nm): R_(t): 3.42 min

¹H-NMR (401 MHz, DMSO-d6 δ=13.36 (s, 1H), 8.50-8.44 (m, 2H), 8.28 (s,1H), 8.0-7.84 (m, 2H), 7.66-7.42 (m, 4H), 7.30-7.21 (m, 2H). MS ESI(M+H) calc 265.1084; found. 265.1080 (C15H12N4O)

N-Propyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=propyl]

HPLC (254 nm): R_(t): 4.29 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.3 (br.s., 1H), 8.53-8.46 (m, 1H), 8.45(dd, J=1.4, 4.7 Hz, 2H), 8.28 (br.s., 1H), 7.98 (s, 1H), 7.83 (m, 1H),7.52-7.40 (m, 2H), 7.50-7.30 (m, 2H), 3.25-3.16 (m, 2H), 1.58-1.46 (m,2H), 0.88 (t, J=7.4 Hz, 3H). MS ESI (M+H) calc 307.1554; found. 307.1555(C18H18N4O).

N-(2-Hydroxy-ethyl)-N-methyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7=2-hydroxy-ethyl;Y=methyl]

HPLC (254 nm): R_(t): 3.51 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.35 (br.s. 1H), 8.46 (d, J=6.0 Hz, 2H),8.25 (br.s., 1H), 7.57-7.35 (m, 4H), 7.26 (br. s., 2H), 4.75 (t, J=5.5Hz, 1H), 3.65-3.40 (m, 4H), 2.93 (m, 3H). MS ESI (M+H) calc 323.1503;found. 323.1515 (C18H18N4O2).

N,N-Dimethyl-3-(4-pyridin-4-yl-1H-pyrazole-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7, Y=methyl]

HPLC (254 nm): R_(t): 3.87 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.35 (br.s. 1H), 8.46 (d, J=5.9 Hz, 2H),8.25 (br.s., 1H), 7.57-7.44 (m, 4H), 7.30-7.23 (m, 2H), 2.96 (br.s. 3H),2.87 (br.s., 3H). MS ESI (M+H) calc 293.1397; found. 293.1387(C17H16N4O).N-(4-Acetylamino-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=4-acetylaminophenyl]

HPLC (254 nm): R_(t): 4.24 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.41 (br.s, 1H), 10.23 (s, 1H), 9.90 (s,1H), 8.48 (dd, J=1.5, 4.6 Hz, 2H), 8.31 (br.s, 1H), 8.10-7.92 (m, 2H),7.69-7.48 (m, 6H), 7.30 (d, J=4.3 Hz, 2H), 2.04 (s, 3H). MS ESI (M+H)calc 398.1612; found. 398.1617 (C23H19N5O2).

N-(1-Phenyl-ethyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=1-phenylethyl]

HPLC (254 nm): R_(t): 5.13 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.36 (br.s, 1H), 8.85 (d, J=7.9 Hz, 1H),8.45 (d, J=6.1 Hz, 2H), 8.28 (br.s, 1H), 8.00-7.21 (m, 11H), 5.16 (quin,J=7.6 Hz, 1H), 1.46 (d, J=7.1 Hz, 3H). MS ESI (M+H) calc 369.1710;found. 369.1724 (C23H20N4O).

3-(4-Pyridin-4-yl-1H-pyrazole-3-yl)-N-(3-trifluoromethyl-phenyl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H;R7=3-trifluoromethylphenyl]

HPLC (254 nm): R_(t): 5.89 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.41 (br.s, 1H), 10.59 (br.s, 1H), 8.46 (d,J=6.1 Hz, 2H), 8.29 (br.s, 1H), 8.00-7.45 (m, 8H), 7.30-7.23 (m, 2H). MSESI (M+H) calc 409.1271; found. 409.1282 (C22H15F3N4O).

N-(2-fluoro-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=2-fluorophenyl]

HPLC (254 nm): R_(t): 5.00 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.34 (br.s, 1H), 10.18 (br.s, 1H), 8.46 (m,2H), 8.17 (br.s, 1H), 8.12 (br.s, 1H), 8.0 (m, 1H), 7.60-7.56 (m, 3H),7.31-7.19 (m, 5H). MS ESI (M+H) calc 359.1303; found. 359.1308(C21H15FN4O).

N-Ethyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=ethyl]

HPLC (254 nm): R_(t): 3.96 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.34 (s, 1H), 8.51 (br.s, 1H), 8.46 (d,J=6.1 Hz, 2H), 8.30 (s, 1H), 7.98 (s, 1H), 7.85 (br.s, 1H), 7.60-7.45(m, 2H), 7.27 (d, J=5.1 Hz, 2H), 1.12 (t, J=7.2 Hz, 3H), 8.46 (d, J=6.1Hz, 2H), 7.27 (d, J=5.1 Hz, 2H), 3.29 (m, 2H), 1.12 (t, J=7.2 Hz, 3H).MS ESI (M+H) calc 293.1397; found. 293.1392 (C17H16N4O)

N-Methyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=methyl]

HPLC (254 nm): R_(t): 3.62 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.36 (s, 1H), 8.53-8.42 (m, 3H), 8.28 (s,1H), 7.97 (br.s. 1H), 7.86-7.81 (br.s, 1H), 7.62-7.44 (m, 2H), 7.27-7.21(m, 2H), 2.78 (m, 3H). MS ESI (M+H) calc 279.1241; found. 279.1241(C16H14N4O)

N-Hydroxy-3-(4-Pyridin-4-Yl-1H-Pyrazol-3-Yl)-Benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=hydroxy]

HPLC (254 nm): R_(t): 3.33 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.37 (s, 1H), 11.24 (s, 1H), 9.04 (s, 1H),8.50-8.44 (m, 2H), 8.25 (s, 1H), 8.10-7.45 (m, 4H), 7.29-7.22 (m, 2H).MS ESI (M+H) calc 281.1033; found. 281.1022 (C15H12N4O2)

3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-N-(4-trifluoromethyl-phenyl)-benzamide(Cmpd. 46)

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H;R7=4-trifluoromethylphenyl]

HPLC (254 nm): R_(t): 5.95 min

MS ESI (M+H) calc 409.1271; found. 409.1281 (C22H15F3N4O).

N-tert-Butyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=tert-butyl]

HPLC (254 nm): R_(t): 4.82 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.33 (s, 1H), 8.47-8.43 (m, 2H), 8.26 (s,1H), 8.03-7.39 (m, 5H), 7.19-7.19 (m, 2H), 1.36 (s, 9H). MS ESI (M+H)calc 321.1710; found. 321.1716 (C19H20N4O)

N-Isothiazol-3-yl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=isothiazol-3-yl]

HPLC (254 nm): R_(t): 4.58 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.45 (s, 1H), 8.52-8.44 (m, 2H), 8.22 (s,1H), 8.02-7.56 (m, 5H), 7.53 (d, J=3.5 Hz, 1H), 7.30-7.25 (m, 2H), 7.24(d, J=3.4 Hz, 1H). MS ESI (M+H) calc 348.0914; found. 348.0915(C18H13N5OS)

N-Benzyl-N-methyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7=benzyl, Y=methyl]

HPLC (254 nm): R_(t): 5.01 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.39 (s, 1H), 8.55-8.40 (m, 2H), 8.27 (s,1H), 7.66-7.04 (m, 11H), 4.65 (br.s, 2H), 2.79 (s, 3H). MS ESI (M+H)calc 369.1710; found. 369.1714 (C23H20N4O)

N-(3-Methoxy-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=3-methoxyphenyl]

HPLC (254 nm): R_(t): 5.12 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.39 (s, 1H), 10.24 (s, 1H), 8.46 (d, J=5.6Hz, 2H), 8.29 (s, 1H), 8.02-7.18 (m, 9H), 6.68 (d, J=8.4 Hz, 1H), 3.75(s, 3H). MS ESI (M+H) calc 371.1503; found. 371.1513 (C22H18N4O2)

N-Furan-2-yl-methyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=furan-2-yl]

HPLC (254 nm): R_(t): 4.53 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.36 (s, 1H), 9.00 (t, J=5.7 Hz, 1H), 8.44(d, J=6.0 Hz, 2H), 8.27 (s, 1H), 8.07-7.43 (m, 5H), 7.28-7.19 (m, 2H),6.40-6.38 (m, 1H), 6.28-6.21 (m, 1H), 4.45 (d, J=4.9 Hz, 2H). MS ESI(M+H) calc 345.1346; found. 345.1351 (C20H16N4O2)

N-Cyclohexyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=cyclohexyl]

HPLC (254 nm): R_(t): 5.10 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.35 (s, 1H), 8.48-8.41 (m, 2H), 8.30-8.18(m, 2H), 7.98 (br.s, 1H), 7.88-7.79 (m, 1H), 7.61-7.37 (m, 2H),7.29-7.18 (m, 2H), 3.76 (m, 1H), 1.94-1.00 (m, 10H). MS ESI (M+H) calc347.1867; found. 347.1874 (C21H22N4O)

N-(4-Chloro-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide (Cpnd.3)

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=4-chlorophenyl]

HPLC (254 nm): R_(t): 5.60 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.40 (s, 1H), 10.42 (s, 1H), 8.50-8.44 (m,2H), 8.29 (s, 1H), 8.09 (s, 1H), 8.10-7.94 (m, 1H), 7.84-7.78 (m, 2H),7.68-7.52 (m, 2H), 7.44-7.38 (m, 2H), 7.31-7.22 (m, 2H). MS ESI (M+H)calc 375.1007; found. 375.1020 (C21H15ClN4O)

N-(4-Methoxy-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=4-methoxyphenyl]

HPLC (254 nm): R_(t): 4.97 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.43 (s, 1H), 10.17 (s, 1H), 8.49-8.45 (m,2H), 8.23 (br. s., 1H), 8.08 (s, 1H), 7.98 (br. s., 1H), 7.70-7.64 (m,2H), 7.60-7.53 (m, 2H), 7.29-7.25 (m, 2H), 6.97-6.89 (m, 2H), 3.75 (s,3H). MS ESI (M+H) calc 371.1503; found. 371.1512 (C22H18N4O2).

N-Butyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=butyl]

HPLC (254 nm): R_(t): 4.73 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.43 (s, 1H), 8.47 (br. s., 1H), 8.46-8.43(m, 2H), 8.28 (s, 1H), 8.03-7.7 (m, 2H), 7.60-7.42 (m, 2H), 7.24 (d,J=4.0 Hz, 2H), 3.28-3.20 (m, 2H), 1.55-1.44 (m, 2H), 1.36-1.26 (m, 2H),0.90 (t, J=7.3 Hz, 3H). MS ESI (M+H) calc 321.1710; found. 321.1709(C19H20N4O).

N-(4-Fluoro-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=4-fluorophenyl]

HPLC (254 nm): R_(t): 5.17 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.40 (s, 1H), 10.35 (s, 1H), 8.48-8.44 (m,2H), 8.29 (s, 1H), 8.13-7.92 (m, 2H), 7.82-7.73 (m, 2H), 7.67-7.51 (m,2H), 7.31-7.23 (m, 2H), 7.22-7.15 (m, 2H). MS ESI (M+H) calc 359.1303;found. 359.1305 (C21H15FN4O)

N-(4-Fluoro-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=3-fluorophenyl]

HPLC (254 nm): R_(t): 5.31 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.41 (s, 1H), 10.48 (s, 1H), 8.47 (dd,J=1.5, 4.6 Hz, 2H), 8.30 (s, 1H), 8.11-7.92 (m, 2H), 7.74 (dt, J=2.3,11.8 Hz, 1H), 7.68-7.53 (m, 3H), 7.39 (q, J=7.9 Hz, 1H), 7.30-7.24 (m,2H), 6.98-6.90 (m, 1H). MS ESI (M+H) calc 359.1303; found. 359.1311(C21H15FN4O)

N-Phenyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=phenyl]

HPLC (254 nm): R_(t): 5.03 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.40 (s, 1H), 10.29 (s, 1H), 8.47 (d, J=6.0Hz, 2H), 8.29 (s, 1H), 8.09 (s, 1H), 8.08-7.92 (m, 1H), 7.80-7.73 (m,1H), 7.70-7.53 (m, 2H), 7.40-7.31 (m, 2H), 7.30-7.23 (m, 1H), 7.29 (br.s., 2H), 7.15-7.07 (m, 1H). MS ESI (M+H) calc 341.1397; found. 341.1399(C21H16N4O).

N-Isobutyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=i-butyl]

HPLC (254 nm): R_(t): 4.67 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.36 (s, 1H), 8.49 (br. s., 1H), 8.45 (d,J=5.9 Hz, 2H), 8.27 (s, 1H), 7.97 (s, 1H), 7.88-7.80 (m, 1H), 7.58-7.42(m, 2H), 7.28-7.22 (m, 2H), 3.07 (t, J=6.1 Hz, 2H), 1.83 (dt, J=6.8,13.4 Hz, 1H), 0.87 (d, J=6.7 Hz, 6H). MS ESI (M+H) calc 321.1710; found.321.1707 (C19H20N4O)

N-Isopropyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=i-propyl]

HPLC (254 nm): R_(t): 4.32 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.36 (s, 1H), 8.45 (d, J=6.0 Hz, 2H), 8.28(s, 1H), 8.25 (s, 1H), 8.01-7.96 (m, 1H), 7.95-7.81 (m, 1H), 7.60-7.40(m, 2H), 7.29-7.24 (br.s. 2H), 4.04-4.16 (m, 1H), 1.16 (d, J=6.6 Hz,6H). MS ESI (M+H) calc 307.1554; found. 307.1543 (C18H18N4O)

N-Allyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=allyl]

HPLC (254 nm): R_(t): 4.18 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.36 (s, 1H), 8.70 (br. s., 1H), 8.47-8.42(m, 2H), 8.28 (s, 1H), 8.00 (s, 1H), 7.90-7.84 (m, 1H), 7.62-7.41 (m,2H), 7.28-7.20 (br. s., 2H), 5.89 (dddd, J=5.2, 5.4, 10.3, 17.2 Hz, 1H),5.04-5.20 (m, 2H), 3.89 (br. s., 2H). MS ESI (M+H) calc 305.1397; found.305.1383 (C18H16N4O)

N-(3-Chloro-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=3-chlorophenyl]

HPLC (254 nm): R_(t): 5.62 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.36 (s, 1H), 10.45 (s, 1H), 8.47 (d, J=6.0Hz, 2H), 8.30 (s, 1H), 8.09 (s, 1H), 8.07-7.97 (m, 1H), 7.96 (t, J=2.0Hz, 1H), 7.71 (dd, J=1.1, 8.2 Hz, 1H), 7.67-7.52 (m, 2H), 7.39 (t, J=8.0Hz, 1H), 7.26 (d, J=4.6 Hz, 2H), 7.17 (d, J=7.6 Hz, 1H). MS ESI (M+H)calc 375.1007; found. 375.1007 (C21H15ClN4O)

3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-N-o-tolyl-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=2-methylphenyl]

HPLC (254 nm): R_(t): 4.99 min

¹H-NMR (401 MHz, DMSO-d₆ δ=13.36 (s, 1H), 9.89 (s, 1H), 8.51-8.40 (m,2H), 8.27 (s, 1H), 8.08-7.92 (m, 1H), 7.69-7.11 (m, 9H), 2.19 (s, 3H).MS ESI (M+H) calc 355.1554; found. 355.1563 (C22H18N4O)

3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-N-p-tolyl-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=4-methylphenyl]

HPLC (254 nm): R_(t): 5.35 min

¹H NMR (401 MHz, DMSO-d₆)) δ=13.39 (s, 1H), 10.21 (s, 1H), 8.46 (dd,J=1.4, 4.6 Hz, 2H), 8.29 (s, 1H), 8.08 (s, 1H), 8.06-7.92 (m, 1H), 7.64(d, J=8.4 Hz, 2H), 7.62-7.52 (m, 2H), 7.30-7.23 (br. s., 2H), 7.16 (d,J=8.3 Hz, 2H), 2.29 (s, 3H). MS ESI (M+H) calc 355.1554; found. 355.1566(C22H18N4O)

N-(2-Methoxy-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=2-methoxyphenyl]

HPLC (254 nm): R_(t): 5.24 min

¹H NMR (401 MHz, DMSO-d₆)) δ=13.39 (s, 1H), 9.42 (s, 1H), 8.47 (d, J=6.0Hz, 2H), 8.29 (s, 1H), 8.06 (br. s., 1H), 8.04-7.92 (m, 1H), 7.76 (d,J=7.7 Hz, 1H), 7.67-7.51 (m, 2H), 7.28 (br. s., 2H), 7.22-7.15 (m, 1H),7.12-7.06 (m, 1H), 6.97 (t, 1H), 3.82 (s, 3H). MS ESI (M+H) calc371.1503; found. 371.1508 (C22H18N4O2)

N-(4-Methoxy-phenyl)-N-methyl-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7=4-methoxyphenyl,Y=methyl]

HPLC (254 nm): R_(t): 4.85 min

¹H NMR (401 MHz, DMSO-d₆)) δ=13.29 (s, 1H), 8.48-8.41 (m, 2H), 8.21 (s,1H), 7.35 (br.s., 1H), 7.30-7.17 (m, 3H), 7.14-7.02 (m, 4H), 6.87-6.78(m, 2H), 3.67 (s, 3H), 3.31 (s, 3H). MS ESI (M+H) calc 385.1659; found.385.1674 (C23H20N4O2).

N-(4-tert-Butyl-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide(Cpnd. 4) [(I)K, X═CH

R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=4-tert-butylphenyl]

HPLC (254 nm): R_(t): 6.27 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.40 (s, 1H), 10.22 (s, 1H), 8.49-8.44 (m,2H), 8.29 (br.s, 1H), 8.09 (s, 1H), 8.07-7.93 (br.s, 1H), 7.71-7.65 (m,2H), 7.64-7.41 (m, 3H), 7.37 (d, J=8.7 Hz, 2H), 7.27 (d, J=4.8 Hz, 1H),1.29 (s, 9H). MS ESI (M+H) calc 397.2023; found. 397.2035 (C25H24N4O)

3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-N-m-tolyl-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=3-methylphenyl]

HPLC (254 nm): R_(t): 5.36 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.40 (s, 1H), 10.21 (s, 1H), 8.48-8.44 (m,2H), 8.29 (s, 1H), 8.08 (s, 1H), 8.01-7.93 (m, 2H), 7.67-7.51 (m, 3H),7.31-7.19 (m, 3H), 6.96-6.89 (m, 1H), 2.31 (s, 3H). MS ESI (M+H) calc355.1554; found. 355.1560 (C22H18N4O).

3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-N-thiophen-2-yl-methyl-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H;R7=thiophen-2-yl-methyl]

HPLC (254 nm): R_(t): 4.76 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.37 (s, 1H), 9.18 (t, J=5.7 Hz, 1H), 8.45(d, J=6.0 Hz, 2H), 8.28 (br.s, 1H), 8.11-7.83 (m, 2H), 7.65-7.43 (m,2H), 7.38 (d, J=5.0 Hz, 1H), 7.28-7.17 (m, 2H), 7.00 (d, J=2.3 Hz, 1H),6.90-6.98 (m, 1H), 4.55-4.68 (m, 2H). MS ESI (M+H) calc 361.1118; found.361.1125 (C20H16N4OS)

N-(3-Acetylamino-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide

[(I)K, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; Y═H; R7=3-acetylamino]

HPLC (254 nm): R_(t): 4.38 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.39 (s, 1H), 10.30 (s, 1H), 9.95 (s, 1H),8.48-8.43 (m, 2H), 8.29 (br.s, 1H), 7.67-7.22 (m, 7H), 7.31-7.22 (m,3H), 2.05 (s, 3H). MS ESI (M+H) calc 398.1612; found. 398.1619(C23H19N5O2).

Example 17 Thiophene-3-sulfonic acid3-(4-pyridin-4-yl-1H-pyrazol-3-yl)benzylamide

[(I)L, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=3-thiophenyl]

Method N Step a:3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3yl]-benzonitrile

Cesium carbonate (8.34 g, 25.6 mmol) and(2-chloromethoxy-ethyl)-trimethyl-silane (1.71 g, 10.24 mmol) were addedto a solution of 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzonitrile (2.10g, 8.54 mmol) in dry DMF (70 ml) and the reaction mixture was stirred atroom temperature under nitrogen atmosphere for 24 h. A further additionof (2-chloromethoxy-ethyl)-trimethyl-silane (0.57 g, 3.41 mmol) wasrequired to affect reaction completion; the solvent was then removedunder reduced pressure and the residue was taken up with DCM (50 ml).The organic layer was washed with a saturated NaHCO₃ solution (1×50 ml),brine (1×50 ml), dried over Na₂SO₄. The filtrate was evaporated todryness to give a brown oil, which was purified by flash chromatography,over silica gel, using DCM/MeOH/NH₄OH (9.8:0.2:0.1) as eluent, to afford3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzonitrile(2.57 g, 6.82 mmol, 80%).

HPLC (254 nm): R_(t): 7.19 min

1H NMR (401 MHz, DMSO-d₆) δ=8.52 (m, 2H), 8.44 (br.s., 1H), 7.90-7.87(m, 1H), 7.84-7.80 (m, 1H), 7.77-7.72 (m, 1H), 7.63 (t, J=8.0 Hz, 1H),7.25-7.23 (m, 2H), 5.51 (s, 2H), 3.68 (t, J=8.0 Hz, 2H), 0.90 (t, J=8.0Hz, 2H), −0.01 (s, 9H). MS ESI (M+H) calc 377.1792; found. 377.1798(C21H24N4OSi).

Method I Step c:3-[4-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzylamine

Lithium aluminium hydride (1 M in THF, 68.2 mmol, 10 eq) was added to asolution of3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzonitrile(2.57 g, 6.82 mmol) in dry THF (45.0 mL) under nitrogen and the reactionmixture was stirred at reflux for 3 hours. The reaction was cooled downin an ice bath and distilled water was added dropwise followed by a 1MNaOH solution (7.5 ml). The organic layer was removed under vacuum andDCM was added (30 ml) to the water phase. The dichloromethane layer waswashed with brine and dried over Na₂SO₄. The filtrate was evaporated todryness to give an oil, which was purified over silica gel, usingDCM/MeOH/NH₄OH (9.8:0.2:0.05) as eluent, to afford3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzylamine(1.48 g, 3.90 mmol, 56%).

HPLC (254 nm): R_(t): 5.12 min

¹H NMR (401 MHz, DMSO-d₆) δ=8.48-8.46 (m, 2H), 8.40 (s, 1H), 7.53-7.30(m, 3H), 7.25-7.14 (m, 3H), 5.48 (s, 2H), 3.73 (br.s, 2H), 3.67 (t,J=8.0 Hz, 2H), 0.89 (t, J=8.0 Hz, 2H), −0.02 (s, 9H). MS ESI (M+H) calc381.2105; found. 381.2122 (C21H28N4OSi).

3-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-benzylamine was an importantside product (20%), which was also isolated and characterized.

3-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-benzylamine

HPLC (254 nm): R_(t): 3.36 min

¹H NMR (401 MHz, DMSO-d₆) δ=8.42-8.48 (m, 2H), 8.20 (s, 1H), 7.52 (s,1H), 7.40-7.32 (m, 2H), 7.23 (m, 1H), 7.22-7.20 (m, 2H), 3.32. (s, 2H),3.94 (s, 3H). MS ESI (M+H) calc 265.1448; found. 265.1450 (C16H16N4). MSESI (M+H) calc 265.1448; found. 265.1450 (C16H16N4).

Method I, Step d and Method M, Step a: General Procedure

The proper sulfonyl chloride (0.184 mmol, 2 eq) was added to a solutionof3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzylamine(0.035 g, 0.092 mmol) in dry DCM (1 ml) and the reaction mixture wasstirred at room temperature for 24 h. The solvent was removed at GenevacEvaporator affording the SEM protected intermediate, which was thenstirred in HCl 4M in dioxane (1 mL) for 24 h at room temperature. Thesolvent was evaporated at Genevac and the crude was purified by reversephase HPLC, affording the final sulfonylamide.

The following sulfonamides were prepared following this procedure:

Thiophene-3-sulfonic acid 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)benzylamide

[(I)L, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=3-thiophenyl]

HPLC (254 nm): R_(t): 4.81 min

¹H NMR (401 MHz, DMSO-d₆) (selected signals) δ=8.46-8.34 (m, 2H), 8.09(s, 1H), 7.94 (br.s, 1H), 7.61 (dd, J=3.0, 5.1 Hz, 1H), 7.41 (s, 1H),7.32-7.28 (m, 2H), 7.26-7.22 (m, 3H), 7.21-7.18 (m, 1H), 4.01 (s, 2H).MS ESI (M+H) calc 397.0788; found. 397.0782 (C19H16N4O2S₂).

Thiophene-2-sulfonic acid 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzylamide

[(I)L, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=2-thiophenyl]

HPLC (254 nm): R_(t): 4.89 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.28 (br.s, 1H), 8.43 (d, J=6.0 Hz, 2H),8.38 (t, J=6.0 Hz, 1H), 8.24 (br.s., 1H), 7.90 (dd, J=1.3, 5.0 Hz, 1H),7.57 (dd, J=1.3, 3.7 Hz, 1H), 7.47-7.19 (m, 6H), 7.15 (dd, J=3.8, 4.8Hz, 1H), 4.06 (m, 2H). MS ESI (M+H) calc 397.0788; found. 397.0795(C19H16N4O2S₂).

3-Fluoro-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]benzenesulfonamide

[(I)L, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=3-fluorophenyl]

HPLC (254 nm): R_(t): 5.15 min.

¹H NMR (401 MHz, DMSO-d₆) δ=13.28 (s, 1H), 8.43 (dd, J=1.5, 4.6 Hz, 2H),8.33 (t, J=6.0 Hz, 1H), 8.24 (s, 1H), 7.65-7.15 (m, 10H), 4.05 (d, J=6.2Hz, 2H). MS ESI (M+H) calc 409.1129; found. 409.1147 (C21H17FN4O2S).

Furan-2-sulfonic acid 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)benzylamide

[(I)L, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=2-furyl]

HPLC (254 nm): R_(t): 4.72 min

MS ESI (M+H) calc 381.1016; found. 381.1027 (C19H16N4O3S).

N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-benzenesulfonamide

[(I)L, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=phenyl]

HPLC (254 nm): R_(t): 4.96 min

MS ESI (M+H) calc 391.1223; found. 391.1215 (C21H18N4O2S)

4-Chloro-N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-benzenesulfonamide

[(I)L, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-chlorophenyl]

HPLC (254 nm): R_(t): 5.40 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.32 (s, 1H), 8.47-8.43 (m, 2H), 8.13 (br.s., 1H), 7.81-7.76 (m, 2H), 7.66-7.59 (m, 2H), 7.39 (s, 1H), 7.25-7.22(m, 2H), 7.35-7.20 (m, 3H), 4.03 (s, 2H). MS ESI (M+H) calc 425.0834;found. 425.0853 (C21H17ClN4O2S)

N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-3-trifluoromethyl-benzenesulfonamide

[(I)L, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=3-trifluoromethylphenyl]

HPLC (254 nm): R_(t): 5.63 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.29 (s, 1H), 8.46-8.41 (m, 2H), 8.40-8.34(br.s, 1H), 8.12 (br. s., 1H), 8.09-8.02 (m, 2H), 7.98 (d, J=7.9 Hz,1H), 7.79 (t, J=7.8 Hz, 1H), 7.38 (s, 1H), 7.33-7.23 (m, 3H), 7.22 (dd,J=1.6, 4.5 Hz, 2H), 4.07 (s, 2H). MS ESI (M+H) calc 459.1097; found.459.1096 (C22H17F3N4O2S).

N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-4-trifluoromethyl-benzenesulfonamide

[(I)L, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-trifluoromethylphenyl]

HPLC (254 nm): R_(t):5.70 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.29 (s, 1H), 8.47-8.41 (m, 2H), 8.41-8.33(br.s, 1H), 8.13 (br.s., 1H), 8.01-7.91 (m, 4H), 7.40 (s, 1H), 7.34-7.25(m, 3H), 7.25-7.22 (m, 2H), 4.06 (s, 2H). MS ESI (M+H) calc 459.1097;found. 459.1086 (C22H17F3N4O2S)

3,5-Difluoro-N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-benzenesulfonamide

[(I)L, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=3,5-difluorophenyl]

HPLC (254 nm): R_(t) 5.33 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.31 (br. s., 1H), 8.47-8.42 (m, 2H),8.41-8.30 (br.s, 1H), 8.13 (br. s., 1H), 7.57-7.51 (m, 1H), 7.47-7.41(m, 2H), 7.39 (br.s, 1H), 7.34-7.29 (m, 1H), 7.29-7.20 (m, 4H), 4.10 (s,2H). MS ESI (M+H) calc 427.1035; found: 427.1038 (C21H16F2N4O2S)

2,5-Difluoro-N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-benzenesulfonamide

[(I)L, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=2,5-difluorophenyl]

HPLC (254 nm): R_(t) 5.16 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.28 (s, 1H), 8.71 (br. s., 1H), 8.47-8.42(m, 2H), 8.12 (br. s., 1H), 7.52-7.35 (m, 3H), 7.33-7.25 (m, 4H),7.24-7.21 (m, 2H), 4.16 (s, 2H). MS ESI (M+H) calc 427.1035; found.427.1040 (C21H16F2N4O2S).

Pyridine-4-sulfonicacid-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-benzylamide

[(I)L, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=pyridyl]

HPLC (254 nm): R₁ 4.29 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.32 (br. s., 1H), 8.91 (dd, J=0.7, 2.4 Hz,1H), 8.77 (dd, J=1.6, 4.9 Hz, 1H), 8.62-8.31 (br.s., 1H), 8.46-8.44 (m,2H), 8.23-7.91 (m, 2H), 7.58 (ddd, J=0.8, 4.8, 8.0 Hz, 1H), 7.40 (s,1H), 7.34-7.18 (m, 5H), 4.10 (s, 2H). MS ESI (M+H) calc 392.1176; found.392.1195 (C20H17N5O2S).

By removing the SEM protective group before derivatization the followingprimary amine was obtained:

3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-benzylamine

HPLC (254 nm): R_(t): 2.42 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.26 (br.s, 1H), 8.46-8.42 (m, 2H), 8.10(br. s., 1H), 7.46-7.44 (m, 1H), 7.42-7.30 (m, 2H), 7.28-7.24 (m, 2H),7.22 (dt, J=1.8, 6.6 Hz, 1H), 3.74 (s, 2H). MS ESI (M+H) calc 251.1291;found. 251.1288 (C15H14N4).

Example 181-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-3-(3-trifluoromethyl-phenyl)-urea[(I)N, X═CH

R1, R2, R3, R4, R5, R6=H; m=0; R7′=3-trifluoromethylphenyl]

Method I, Step d and Method M, Step a

3-Trifluoromethylphenylisocyanate (0.184 mmol, 2 eq) was added to asolution of3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzylamine(0.035 g, 0.092 mmol) (prepared as described in Example 19) in dry DCM(1 ml) and the reaction mixture was stirred at room temperature for 24h. The solvent was removed at Genevac Evaporator affording the SEMprotected intermediate, which was then stirred in HCl 4M in dioxane (1mL) for 24 h at room temperature. The solvent was evaporated at Genevacand the crude was purified by reverse phase HPLC, affording the finalurea.

HPLC (254 nm): R_(t): 5.62 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.32 (br.s, 1H), 8.95 (s, 1H), 8.44-8.39(m, 2H), 8.12 (br.s, 1H), 7.96 (s, 1H), 7.54-7.21 (m, 9H), 6.82 (t,J=5.9 Hz, 1H), 4.33 (d, J=5.9 Hz, 2H). MS ESI (M+H) calc 438.1536;found. 438.1535 (C23H18F3N5O).

Operating in an analogous way the following compounds were prepared:

1-(4-Chloro-3-trifluoromethylphenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-urea

[(I)N, X═CH; R1, R2, R3, R4, R5, R6=H; m=0;R7′=4-chloro-3-trifluoromethylphenyl]

HPLC (254 nm): R_(t):4.97 min

¹H NMR (401 MHz, DMSO-d₆) (selected signals) δ=13.36 (br.s., 1H),8.42-8.39 (m, 2H), 8.11-8.09 (m, 2H), 7.61-7.59 (m, 1H), 7.54 (m, 1H),7.45 (br.s, 1H), 7.41-7.29 (m, 3H), 7.28-7.23 (m, 2H), 4.32 (d, J=6.0Hz, 2H). MS ESI (M+H) calc 472.1147; found. 472.1150 (C23H17ClF3N5O).

1-(4-Chloro-3-trifluoromethylphenyl)-3-[3-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-urea

[(I)N, X═CH; R2, R3, R4, R5, R6=H; m=0; R1=methyl;R7′=4-chloro-3-trifluoromethylphenyl]

HPLC (254 nm): R_(t): 6.36 min

¹H NMR (500 MHz, DMSO-d₆) δ=9.07 (s, 1H), 8.41 (dd, J=1.5, 4.5 Hz, 2H),8.19 (s, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.57 (dd, J=2.4, 7.5 Hz, 1H), 7.55(br.s, 1H), 7.43 (br. s., 1H), 7.34-7.28 (m, 2H), 7.21-7.17 (m, 3H),6.87 (t, J=5.9 Hz, 1H), 4.31 (d, J=6.0 Hz, 2H), 3.91 (s, 3H). MS ESI(M+H) calc 486.1303; found: 486.1302 (C24H19ClF3N5O).

1-Phenyl-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-urea

[(I)N, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=phenyl]

HPLC (254 nm): R_(t): 4.77 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.31 (br.s, 1H), 8.53 (s, 1H), 8.44-8.41(m, 2H), 8.12 (br. s., 1H), 7.45 (s, 1H), 7.42-7.18 (m, 9H), 6.92-6.87(m, 1H), 6.64 (t, J=6.0 Hz, 1H), 4.32 (d, J=6.0 Hz, 2H). MS ESI (M+H)calc 370.1663; found. 370.1678 (C22H19N5O).

1-(4-Chloro-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-urea

[(I)N, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-chlorophenyl]

HPLC (254 nm): R_(t): 5.31 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.32 (br. s., 1H), 8.69 (s, 1H), 8.45-8.39(m, 2H), 8.14 (br. s., 1H), 7.46-7.20 (m, 10H), 6.70 (t, J=5.9 Hz, 1H),4.32 (d, J=6.0 Hz, 2H). MS ESI (M+H) calc 404.1273; found. 404.1277(C22H18ClN5O).

1-(3-Methoxy-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-urea

[(I)N, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=3-methoxyphenyl]

HPLC (254 nm): R_(t): 4.84 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.30 (br. s., 1H), 8.55 (s, 1H), 8.44-8.41(m, 2H), 8.12 (br. s., 1H), 7.44 (s, 1H), 7.41-7.32 (m, 2H), 7.27-7.22(m, 3H), 7.12-7.16 (m, 1H), 7.08-7.12 (m, 1H), 6.87 (dd, J=1.1, 8.2 Hz,1H), 6.65 (t, J=5.9 Hz, 1H), 6.48 (dt, J=1.2, 8.2 Hz, 1H), 4.32 (d,J=6.0 Hz, 2H), 3.71 (s, 3H). MS ESI (M+H) calc 400.1768; found. 400.1767(C23H21N5O2).

1-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-3-p-tolyl-urea

[(I)N, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-methylphenyl]

HPLC (254 nm) R_(t):5.07 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.29 (br. s., 1H), 8.44-8.41 (m, 2H), 8.39(s, 1H), 8.21 (br.s., 1H), 7.48-7.20 (m, 8H), 7.03 (d, J=8.2 Hz, 2H),6.58 (t, J=5.9 Hz, 1H), 4.31 (d, J=6.0 Hz, 2H), 2.22 (s, 3H). MS ESI(M+H) calc 384.1819; found. 384.1803 (C23H21N5O).

1-(3-Fluoro-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-urea

[(I)N, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=3-fluorophenyl]

HPLC (254 nm): R_(t): 5.04 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.32 (br. s., 1H), 8.80 (s, 1H), 8.45-8.38(m, 2H), 8.12 (br. s., 1H), 7.48-7.21 (m, 7H), 7.06-7.02 (m, 2H),6.7-6.73 (m, 1H), 6.73-6.67 (m, 1H), 4.32 (d, J=6.0 Hz, 2H). MS ESI(M+H) calc 388.1568; found. 388.1554 (C22H18FN5O).

1-(4-Fluoro-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-urea

[(I)N, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-fluorophenyl]

HPLC (254 nm): R_(t): 4.91 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.32 (br. s., 1H), 8.57 (s, 1H), 8.46-8.39(m, 2H), 8.12 (br. s., 1H), 7.44 (s, 1H), 7.42-7.32 (m, 4H), 7.30-7.23(m, 3H), 7.01-7.09 (m, 2H), 6.64 (t, J=6.0 Hz, 1H), 4.32 (d, J=5.9 Hz,2H).

MS ESI (M+H) calc 388.1568; found. 388.1577 (C22H18FN5O).

1-(2,4-Difluoro-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-urea

[(I)N, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=2,4-difluorophenyl]

HPLC (254 nm): R_(t): 5.03 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.31 (br. s., 1H), 8.41 (d, J=6.2 Hz, 2H),8.32 (d, J=1.6 Hz, 1H), 8.11 (br. s., 1H), 8.04 (td, J=6.3, 9.3 Hz, 1H),7.43 (s, 1H), 7.41-7.26 (m, 4H), 7.24 (d, J=6.2 Hz, 2H), 7.04-6.94 (m,2H), 4.32 (d, J=5.9 Hz, 2H). MS ESI (M+H) calc 406.1474; found. 406.1467(C22H17F2N5O).

1-(4-Methoxy-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-urea

[(I)N, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-methoxyphenyl]

HPLC (254 nm): R_(t): 4.69 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.31 (br. s., 1H), 8.42 (d, J=6.1 Hz, 2H),8.31 (s, 1H), 8.11 (br. s., 1H), 7.43 (s, 1H), 7.41-7.22 (m, 7H), 6.81(d, J=9.0 Hz, 2H), 6.53 (t, J=5.9 Hz, 1H), 4.30 (d, J=6.0 Hz, 2H), 3.69(s, 3H).

MS ESI (M+H) calc 400.1768; found. 400.1764. (C23H21N5O2).

1-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-3-m-tolyl-urea

[(I)N, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=3-methylphenyl]

HPLC (254 nm): R_(t): 5.08 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.30 (br. s., 1H), 8.45 (s, 1H), 8.42 (d,J=6.2 Hz, 2H), 8.11 (br. s., 1H), 7.43 (s, 1H), 7.40-7.21 (m, 6H), 7.16(d, J=83.0 Hz, 1H), 7.08 (t, J=7.7 Hz, 1H), 6.71 (m, 1H), 6.64 (t, J=5.9Hz, 1H), 4.30 (d, J=5.9 Hz, 2H), 2.24 (s, 3H). MS ESI (M+H) calc384.1819; found. 384.1830 (C23H21N5O).

1-(2-Fluoro-4-trifluoromethyl-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-urea

[(I)N, X═CH; R1, R2, R3, R4, R5, R6=H; m=0;R7′=2-fluoro-4-trifluoromethylphenyl]

HPLC (254 nm): R_(t): 5.77 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.31 (br. s., 1H), 8.72 (br. s., 1H), 8.39(d, J=6.1 Hz, 2H), 8.11 (br. s., 1H), 7.48-7.18 (m, 10H), 4.35 (d, J=5.7Hz, 2H). MS ESI (M+H) calc 456.1442; found. 456.1436 (C23H17F4N5O).

1-(4-Cyano-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-urea

[(I)N, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-cyanophenyl]

HPLC (254 nm): R_(t):4.88 min

¹H NMR (401 MHz, DMSO-d₆) δ=13.29 (br. s., 1H), 9.12 (br. s., 1H),8.46-8.35 (m, 2H), 8.11 (br. s., 1H), 7.70-7.63 (m, 2H), 7.60-7.53 (m,2H), 7.43 (s, 1H), 7.40-7.21 (m, 5H), 6.90 (t, J=5.9 Hz, 1H), 4.33 (d,J=5.9 Hz, 2

H). MS ESI (M+H) calc 395.1615; found. 395.1620 (C23H18N6O).

1-(4-Cyano-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-urea

[(I)N, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-trifluoromethylphenyl]

HPLC (254 nm): R_(t): 5.67 min

¹H NMR (401 MHz, DMSO-d6) δ=13.31 (br. s., 1H), 8.99 (s, 1H), 8.41 (d,J=6.2 Hz, 2H), 8.12 (br. s., 1H), 7.62-7.53 (m, 4H), 7.44 (s, 1H),7.41-7.22 (m, 5H), 6.81 (t, J=5.9 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H). MSESI (M+H) calc 438.1536; found. 438.1547 (C23H18F3N5O).

1-Benzol[1,3]dioxol-5-yl-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-urea

[(I)N, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=benzol[1,3]dioxol-5-yl]

HPLC (254 nm): R_(t): 4.69 min

¹H NMR (401 MHz, DMSO-d6) δ=13.28 (s, 1H), 8.42-8.40 (m, 2H), 8.25 (s,1H), 7.49-7.18 (m, 7H), 7.15 (d, J=1.8 Hz, 1H), 6.76 (d, J=8.3 Hz, 1H),6.67 (dd, J=2.1, 8.4 Hz, 1H), 6.55 (t, J=5.4 Hz, 1H), 5.93 (s, 2H), 4.29(d, J=5.1 Hz, 2H). MS ESI (M+H) calc 414.1561; found. 414.1567(C23H19N5O3).

1-(4-Dimethylamino-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-urea

[(I)N, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7′=4-dimethylaminophenyl]

HPLC (254 nm): R_(t): 4.75 min

¹H NMR (401 MHz, DMSO-d6) δ=13.29 (s, 1H), 8.43 (d, J=6.1 Hz, 2H), 8.26(s, 1H), 8.13 (br.s., 1H), 7.49-7.13 (m, 8H), 6.66 (d, J=9.0 Hz, 2H),6.45 (t, J=5.8 Hz, 1H), 4.29 (d, J=5.9 Hz, 2H), 2.81 (s, 6H). MS ESI(M+H) calc 413.2085; found: 413.2081 (C24H24N6O).

Example 19N-[3-(4-Pyridin-4-yl-1H-pyrazol-3-yl)benzyl]-4-trifluoromethyl-benzamide

[(I)P, X═CH; R1, R2, R3, R4, R5, R6=H; m=0; R7=4-trifluoromethylphenyl]

Method I Step hN-{3-[4-Pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzyl}-4-trifluoromethyl-benzamide

4-Trifluoromethylbenzoylchloride (0.054 g, 0.26 mmol) was added to asolution of3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzylamine(0.10 g, 0.26 mmol) (prepared as described in Example 17) andtriethylamine (0.08 g, 0.79 mmol) in dry DCM (2.0 ml) at 0° C. Thereaction mixture was stirred at room temperature under nitrogenatmosphere for 6 h. The organic layer was washed with water (2.0 mL) anddried over Na₂SO₄. The filtrate was evaporated to dryness to give an oilwhich was purified by flash chromatography, over silica gel, usingdichloromethane/MeOH (98:0.2) as eluent, to affordN-{3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzyl}-4-trifluoromethyl-benzamide(0.110 g, 0.20 mmol, 76%).

Method M

Step a

N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-4-trifluoromethyl-benzamide

N-{3-[4-pyridin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-benzyl}-4-trifluoromethyl-benzamide(0.10 g, 0.19 mmol) was stirred in HCl 4M in dioxane at room temperaturefor 4 h. The solvent was evaporated under vacuum and the crude productwas purified by reverse phase HPLC yieldingN-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyl]-4-trifluoromethyl-benzamide(0.025 g, 0.06 mmol, 31%) as a solid.

HPLC (254 nm): R_(t): 5.54 min

¹H NMR (401 MHz, DMSO-d6) δ=13.42 (br. s, 1H), 9.25 (t, J=5.9 Hz, 1H),8.39 (d, J=6.0 Hz, 2H), 8.24 (br. s., 1H), 8.03 (d, J=8.2 Hz, 2H), 7.85(d, J=8.2 Hz, 2H), 7.5-7.2 (m, 6H), 4.52 (d, J=6.0 Hz, 2H). MS ESI (M+H)calc 423.1427; found. 423.1434 (C23H17F3N4O).

Example 201-{3-[4-(2-aminopyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-3-[4(trifluoromethyl)-phenyl]urea(Cpd. 12)

[(I)U, R1, R3, R4, R5, R6=H; m=0; A=NHCONH; R7=4-trifluoromethylphenyl]

Method A Step e: 1-(3-bromophenyl)-2-pyridin-4-ylethanone

To 66 ml (0.066 mol) of sodium 1,1,1,3,3,3-hexamethyldisilazane 1M inTHF under nitrogen atmosphere at 0° C., 3.2 ml (0.033 mol) of 4-picolinewere added. After stirring for 60 minutes 5 ml (7.15 g; 0.03 mol) ofethyl 3-bromo benzoate were added and the mixture maintained in the sameconditions for 1.5 hours. HCl 2N was then added, the mixture made basicwith NaOH 2N and extracted with ethyl acetate. The organic phase wasdried over Na₂SO₄ and the solvent evaporated. 7.5 g (82% yield) of thetitle compound were obtained by crystallization from AcOEt-Et₂₀.

¹H NMR (401 MHz, DMSO-d6) δ=8.52 (d, J=6.0 Hz, 2H), 8.19 (t, J=1.7 Hz,1H), 8.05 (ddd, J=1.0, 1.6, 7.8 Hz, 1H), 7.89 (ddd, J=1.0, 2.0, 8.0 Hz,1H), 7.54 (t, J=7.9 Hz, 1H), 7.19-7.33 (m, 2H), 4.53 (s, 2H). MS-ESI(M+H) calc. 276.0019 found 276.0023 (C13H10BrNO)

Step f:(2E)-1-(3-bromophenyl)-3-(dimethylamino)-2-pyridin-4-ylprop-2-en-1-one

Dimethylformamide dimethylacetal (15 mL) were added to a solution of 7.2g (0.026 ol) of 1-(3-bromophenyl)-2-pyridin-4-ylethanone in 15 ml of drytetrahydrofuran. After stirring at 65° C. for 6 hours, the solvent wasremoved under reduced pressure. 8 g (93% yield) of the title compound asan oil were obtained and employed in the next step without any furtherpurification.

Step g: 4-[3-(3-bromophenyl)-1H-pyrazol-4-yl]pyridine

8 g (0.024 mol) of1-(3-bromophenyl)-3-(dimethylamino)-2-pyridin-4-ylprop-2-en-1-one weredissolved in 20 ml of ethanol and 3 mL (0.06 mol) of hydrazine hydratewere added. The solution was refluxed under stirring for 4 hours. Thetitle compound was collected by filtration. The filtrate was evaporated,the residue taken up with dichloromethane and washed with water. Theorganic layer, dried over Na₂SO₄, was evaporated to dryness andtriturated with diethylether affording a second crop of the titlecompound (7.2 g overall; 100% yield).

¹H NMR (401 MHz, DMSO-d6) δ=13.50 and 13.40 (2 br. s., 1H, mixture oftautomers), 8.48 (d, J=6.0 Hz, 2H), 8.25 and 7.95 (2 br. s., 1H, mixtureof tautomers), 7.55-7.70 (m, 2H), 7.32-7.48 (m, 2H), 7.26 (d, J=4.8 Hz,2H). MS-ESI (M+H) calc. 300.0131 found 300.0145 (C14H10BrN3).

Step h:4-[3-(3-bromophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine

3 g (0.01 mol) of 4-[3-(3-bromophenyl)-1H-pyrazol-4-yl]pyridine weredissolved in 50 ml of dry dimethylformamide and 3.9 g (0.012 mol) ofcesium carbonate and 1.6 ml (0.012 mol) of p-methoxybenzyl chloride wereadded. The mixture was stirred at 70° C. for 2 hours and the solventremoved in vacuo. The residue was taken up with dichoromethane andwashed with water. The organic phase was dried over Na₂SO₄ andevaporated. Purification by column chromatography(dichloromethane-acetone 95/5) afforded 2 g (48% yield) of the titlecompound as an oil.

¹H NMR (401 MHz, DMSO-d6) (major regioisomer)=8.46-8.53 (m, 2H), 8.30(s, 1H), 7.58 (m, 1H), 7.33-7.38 (m, 5H), 7.19-7.26 (m, 2H), 6.95 (d,J=8.66 Hz, 2H), 5.33 (s, 2H), 3.75 (s, 3H). MS-ESI (M+H) calc. 420.0706found 420.0701 (C22H18BrN30).

Method H Step f:N-(diphenylmethylidene)-3-[1-(4-methoxybenzyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]aniline

1.9 g (4.5 mmol) of4-[3-(3-bromophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridine weredissolved in 60 ml of dry toluene under nitrogen atmosphere and 366 mg(0.4 mmol) of tris(dibenzylidene-acetone)dipalladium(0), 498 mg (0.8mmol) of racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphtalene, 562 mg(5.85 mmol) of sodium tertbutoxide and 975 L (5.85 mmol) ofbenzophenonimine were added to the solution successively. The mixturewas refluxed for 3 hours. After cooling to room temperature the reactionmixture was filtered over a celite pad and the solvent evaporated. Theresidue was redissolved with ethylacetate and washed with water. Theorganic layer was dried over Na₂SO₄ and evaporated again to dryness. Thecrude was purified by chromatography on a silica gel column eluted bydichloromethane-methanol 95/5, affording 1.5 g (65% yield) of the titlecompound.

¹H NMR (401 MHz, DMSO-d6) δ=8.42 (d, J=6.0 Hz, 2H), 8.24 (s, 1H),7.62-7.67 (m, 2H), 7.50-7.56 (m, 1H), 7.43-7.49 (m, 2H), 7.31-7.38 (m,5H), 7.10-7.15 (m, 3H), 7.04-7.07 (m, 2H), 6.91-6.97 (m, 2H), 6.86 (ddd,J=1.1, 1.3, 7.9 Hz, 1H), 6.73 (t, J=1.7 Hz, 1H), 6.65 (ddd, J=1.0, 2.1,7.9 Hz, 1H), 5.28 (s, 2H), 3.75 (s, 3H). MS-ESI (M+H) calc. 521.2336found 521.2328 (C35H28N4O).

Method E Step a:N-(diphenylmethylidene)-3-[1-(4-methoxybenzyl)-4-(1-oxidopyridin-4-yl)-1H-pyrazol-3-yl]aniline

100 mg (0.19 mmol) ofN-(diphenylmethylidene)-3-[1-(4-methoxybenzyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]anilinewere reacted with 36 mg (0.21 mmol) of m-chloroperbenzoic acid in 4 mlof dimethoxyethane. The solution was stirred at room temperatureovernight. The reaction mixture was partitioned between dichloromethaneand aqueous NaHCO₃, the organic layer dried over Na₂SO₄ and the solventremoved under reduced pressure. The residue was triturated withdiethylether and collected by filtration giving 80 mg (78%) of the titlecompound.

¹H NMR (401 MHz, DMSO-d6) (selected signals, major regioisomer) δ=8.20(s, 1H), 8.06-8.10 (m, 2H), 8.07 (m, 1H), 7.12-7.15 (m, 3H), 7.03-7.05(m, 2H), 6.93-6.95 (m, 2H), 6.89 (ddd, J=1.1, 1.3, 7.9 Hz, 1H), 6.73 (t,J=1.7 Hz, 1H), 6.68 (ddd, J=1.0, 2.1, 7.9 Hz, 1H), 5.27 (m, 2H), 3.75(s, 3H). MS-ESI (M+H) calc. 537.2285 found 537.2286 (C35H28N4O2).

Step c:N-tert-butyl-4-[3-{3-[(diphenylmethylidene)amino]phenyl}-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridin-2-amine

200 mg (0.4 mmol) ofN-(diphenylmethylidene)-3-[1-(4-methoxybenzyl)-4-(1-oxidopyridin-4-yl)-1H-pyrazol-3-yl]anilinewere suspended in 50 ml of trifluoromethylbenzene and 210 μl (2 mmol) oftert-butylamine were added under stirring at room temperature. Themixture was cooled to 0° C. and 260 mg (0.8 mmol) of p-toluensulfonicanhydride were added. The reaction was maintained in the same conditionsfor 2.5 hours. Then the same amounts of reactants and 2 ml ofdichloromethane to obtain a clear solution were added and after further2 hours the reaction went to completion. The solvent was evaporated andthe residue taken up in dichloromethane and washed with water. Theorganic phase was dried over Na₂SO₄ and evaporated to dryness, giving161 mg (73% yield) of the title compound.

MS-ESI (M+H) calc. 592.3071 found 592.3065 (C39H37N5O)

Method H Step g:4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-tert-butylpyridin-2-amine

120 mg (0.2 mmol) ofN-tert-butyl-4-[3-{3-[(diphenylmethylidene)amino]phenyl}-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridin-2-aminewere dissolved in 20 ml of 1,4-dioxane and 5 ml of HCl 4M in dioxanewere added. After 4 hours the solvent was removed in vacuo and theresidue dissolved in dichloromethane and washed with aqueous NaHCO₃.

The organic layer was dried over Na₂SO₄ and evaporated to give, aftertrituration with diethylether, 40 mg (46% yield) of the title compound.

Method G Step e:1-(3-{4-[2-(tert-butylamino)pyridin-4-yl]-1-(4-methoxybenzyl)-1H-pyrazol-3-yl}phenyl)-3-[4-(trifluoromethyl)phenyl]urea

40 mg (0,094 mmol) of4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-tert-butylpyridin-2-aminewere dissolved in 2 ml of dry dimethylformamide and 12 μL (0.094 mmol)of p-trifluoromethylphenylisocyanate were added. The solution wasstirred at room temperature for 3 hours. The reaction mixture was thenpoured into water and the product extracted several times withethylacetate. The organic layer was dried over Na₂SO₄ and evaporated todryness. The crude was purified by chromatography on a silica gel columneluted with dichloromethane-acetone 9/1, affording 40 mg (70% yield) ofthe title compound.

¹H NMR (401 MHz, DMSO-d6) δ=9.01 (s, 1H), 8.84 (s, 1H), 8.01 (s, 1H),7.84 (d, J=5.2 Hz, 1H), 7.58-7.69 (m, 3H), 7.55 (t, J=1.8 Hz, 1H),7.47-7.51 (m, 1H), 7.31-7.36 (m, 2H), 7.27 (t, J=7.9 Hz, 1H), 7.00 (ddd,J=1.1, 1.3, 7.9 Hz, 1H), 6.88-6.97 (m, 2H), 6.42 (d, J=0.6 Hz, 1H), 6.26(dd, J=1.4, 5.3 Hz, 1H), 6.02 (s, 1H), 5.31 (s, 2H), 3.75 (s, 3H), 1.33(s, 9H). MS-EI (M+H) calc. 615.2690 found 615.2687 (C34H33F3N6O2).

Method K Step d:1-{3-[4-(2-aminopyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)-phenyl]urea

100 mg (0.16 mmol) of1-(3-{4-[2-(tert-butylamino)pyridin-4-yl]-1-(4-methoxybenzyl)-1H-pyrazol-3-yl}phenyl)-3-[4-(trifluoromethyl)phenyl]ureawere dissolved in 5 ml of trifluoroacetic acid and the mixture heated at70° C. under stirring. After 16 hours the solution was poured into icywater, neutralized with aqueous NaHCO₃ and extracted withdichloromethane. The organic layer was then dried over Na₂SO₄ andevaporated to dryness. The product was purified by chromatography on asilica gel column eluted with dichloromethane-methanol (gradient from 1%to 5%) obtaining 50 mg (71% yield) of the title compound.

¹H NMR (401 MHz, DMSO-d6) (selected signals) δ=13.28 and 13.15 (2 br.s., 1H, mixture of tautomers), 9.10 (br.s., 1H), 8.85 (br.s., 1H), 7.80(d, J=5.4 Hz, 1H), 7.60-7.68 (m, 4H), 7.05 (d, J=7.2 Hz, 1H), 6.41 (br.s., 1H), 6.38 (dd, J=1.4, 5.3 Hz, 1H), 5.83 (br. s., 2H). MS-ESI (M+H)calc. 439.1489 found 439.1490 (C22H17F3N6O).

Example 21N-(4-{3-[3-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-1H-pyrazol-4-yl}pyridin-2-yl)thiophene-2-carboxamide

[(I)V, R1, R3, R4, R5, R6=H; R16=thiophen-2-yl; m=0; A=NHCONH;R7=4-trifluoromethylphenyl]

Method K Step e

To a solution of 40 mg (0.09 mmol) of1-{3-[4-(2-aminopyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)phenyl]urea(prepared as described in Example 20) in 4 ml of dry pyridine 1 mg(0.009 mmol) of 4-dimethylaminopyridine and 38 μl of 2-thienylcarbonylchloride (0.36 mmol) were added. After 16 hours under stirring at roomtemperature the reaction mixture was poured into aqueous NaHCO₃ andextracted with dichloromethane, giving quantitatively (HPLC-MS analysis)N-(4-{1-(thiophen-2-ylcarbonyl)-3-[3-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-1H-pyrazol-4-yl}pyridin-2-yl)thiophene-2-carboxamideas a regioisomeric mixture, that was submitted to the subsequenthydrolysis step without any further purification. The crude was thendissolved in 50 ml of methanol and 5 ml of triethylamine were addedunder stirring at room temperature. After 5 hours the solvent wasremoved in vacuo and the residue taken up with dichloromethane andwashed with water. The product was extracted several times with amixture dichloromethane-methanol 9/1 and then with ethylacetate. Thecrude was chromatographed on a silica gel column eluted with a mixtureDCM/methanol (gradient from 1% to 5%), thus obtaining 40 mg (80% yield)of the title compound.

¹H NMR (401 MHz, DMSO-d6) (selected signals) δ=13.42 and 13.28 (2 br.s.,1H, mixture of tautomers), 10.83 (s, 1H), 9.02-9.08 (2 br.s., 1H),8.89-8.81 (2 br.s., 1H), 8.25 (d, J=5.2 Hz, 1H), 8.22 (d, J=3.54 Hz,1H), 8.18 (m, 1H), 7.86 (d, 1H), 7.58-7.66 (m, 4H), 7.19 (m, 1H),7.02-7.12 (m, 1H), 6.94-7.01 (m, 1H). MS-ESI (M+H) calc. forC27H19F3N6O2S: 549.1315 found 549.1299.

Operating in an analogous way but using only methanol in place of amixture methanol-triethylamine during the hydrolysis step, the followingcompound was obtained:

N-[4-(3-{3-[3-(4-Trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyridin-2-yl]-acetamide(Cmpd. 17)

[(I)V, R1, R3, R4, R5, R6=H; R16=methyl; m=0; A=NHCONH;R7=4-trifluoromethylphenyl]

¹H-NMR (401 MHz, DMSO-d6) δ=13.38 and 13.25 (2 br.s., 1H, mixture oftautomers), 10.38 (s, 1H), 9.13 and 9.07 (2 br.s., 1H, mixture oftautomers), 8.92 and 8.83 (2 br.s., 1H, mixture of tautomers), 8.16 (m,1H), 8.07-8.12 (m, 1H), 7.82 (m, 1H), 7.59-7.68 (m, 4H), 7.47-7.56 (m,1H), 7.34-7.41 (m, 1H), 7.24-7.30 (m, 1H), 7.00-7.07 (m, 1H), 6.88-6.94(m, 1H), 2.05 (s, 3H). MS-ESI (M+H) calc. for C24H19F3N6O2: 481.1595,found 481.1598.

Preparation of dibenzyl-(2,4-difluoro-phenyl)-amine

To 2,4-difluoroaniline (40.0 g, 0.31 mol) in N,N-dimethylformamide (400mL) were added potassium carbonate (120 g, 0.92 mol, 3 eq) and benzylbromide (112 mL, 0.71 mmol, 2.3 eq). The reaction was stirred withmechanical stirring at room temperature overnight. In order to quenchthe benzyl bromide in excess, NH₄OH (90 mL) was added and the reactionwas stirred overnight. The mixture was filtered and DMF was evaporatedunder reduced pressure. Ethyl acetate was added and the organic layerwas washed with water and brine, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure and theoily crude was crystallized in methanol, obtaining after drying 71 g ofdibenzyl-(2,4-difluoro-phenyl)-amine as a white solid (74%)

HPLC (254 nm): R_(t): 8.25

¹H-NMR (401 MHz, DMSO-d6) δ=7.26-7.32 (m, 8H), 7.19-7.25 (m, 2H),7.12-7.19 (m, 1H), 6.97 (td, J=6.0, 9.4 Hz, 1H), 6.82 (tt, J=1.4, 8.6Hz, 1H), 4.24 (s, 4H). HRMS (ESI) calcd for C20H17F2N [M+H]+ 310.1402,found 310.1407.

Preparation of 3-dibenzylamino-2,6-difluoro-benzoic acid benzyl ester

To a solution of dibenzyl-(2,4-difluoro-phenyl)-amine (17.5 g, 0.056mol) in THF (140 mL), under nitrogen atmosphere, cooled at −78° C.,n-butyllithium (1.6 M in hexane, 38 mL, 0.06 mol) was slowly added. Thereaction was stirred for 1 hour, and then quickly added via a cannula toa solution of benzyl chloroformate (11.78 mL, 0.084 mol) in THF (140 mL)previously cooled at −78° C. The reaction was then allowed to warm toroom temperature, poured into water and extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated and purified bysilica gel column chromatography eluting with 5% ethyl acetate in hexanegrading to 10% acetate (quant.).

HPLC (254 nm): R_(t): 8.49

¹H-NMR (401 MHz, DMSO-d6) δ=7.20-7.46 (m, 15H), 7.15 (td, J=5.7, 9.4 Hz,1H), 6.98 (td, J=1.5, 9.2 Hz, 1H), 5.39 (s, 2H), 4.27 (s, 4H)

HRMS (ESI) calcd for C28H23F2NO2 [M+H]+ 444.177, found 444.1765.

Example 22N-[2,4-Difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-benzenesulfonamide(Cmpd. 18)

[(I)C, X═CH; R1, R2, R4, R5=H; R3, R6=F; m=0; R7′=2,5-difluoro-phenyl]

Method A Step e:1-(3-dibenzylamino-2,6-difluoro-phenyl)-2-pyridin-4-yl-ethanone

To 4-methyl-pyridine (806 4, 8.33 mmol) in anhydrous tetrahydrofuran (35mL) was added at 0° C. sodium hexamethyldisilazide 1 M intetrahydrofuran (16.66 mL, 16.66 mmol) and the reaction was stirred for20 minutes. 3-Dibenzylamino-2,6-difluoro-benzoic acid benzyl ester(3.691 g, 8.33 mmol) was dissolved in tetrahydrofuran (5 mL) and addeddropwise to the solution with 4-methyl-pyridine, the reaction wasstirred at 0° C. for one hour. The reaction was poured into saturatedammonium chloride solution and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous sodium sulfate,filtrate and concentrated under reduced pressure. The crude was purifiedby silica gel column chromatography eluting with ethyl acetate 30% inhexane to give the title compound (1.775 g, 50%).

¹H NMR (401 MHz, DMSO-d6) δ=8.50 (d, J=5.9 Hz, 2H), 7.16-7.34 (m, 12H),7.09 (td, J=5.9, 9.3 Hz, 1H), 6.91-6.99 (m, 1H), 4.22-4.30 (M, 6H).

HRMS (ESI) calcd for C27H22F2N20 [M+H]+ 429.1773, found 429.1767.

Step f:1-(3-dibenzylamino-2,6-difluoro-phenyl)-3-dimethylamino-2-pyridin-4-yl-propenone

To 1-(3-dibenzylamino-2,6-difluoro-phenyl)-2-pyridin-4-yl-ethanone(1.775 g, 4.14 mmol) in toluene (40 mL) dimethoxymethyldimethylamine(2.2 mL, 16.5 mmol) was added. The reaction was stirred at 80° C. forone hour and the solvent was concentrated under reduced pressure. Thecrude was used in the next step without further purification.

Step g:Dibenzyl-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amine

To hydrazine 1M in tetrahydrofuran (16.56 mL) was addeddibenzyl-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amine(1.999 g, 4.14 mmol). The reaction was stirred under nitrogen atmosphereat 70° C. for one hour. The reaction was diluted with ethyl acetate (100mL) and washed with water (3×50 mL) and brine (50 mL). The organic layerwas dried over Na₂SO₄ concentrated under reduced pressure until a finalvolume of 5 mL. Ethyl ether was added and the mixture was stirred atroom temperature for 30 minutes. The solid was filtered and dried at 50°C. for 1 h.Dibenzyl-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-aminewas obtained as a pale yellow solid in 76% yield over the last twosteps.

HPLC (254 nm): R_(t): 6.88 min.

¹H NMR (401 MHz, DMSO-d6) (major tautomer) δ=13.53 (br. s., 1H), 8.47(m, 1H), 8.37 (d, J=5.98 Hz, 2H), 7.20-7.35 (m, 10H), 7.10 (d, J=5.98Hz, 2H), 7.02-7.10 (m, 1H), 6.91-6.98 (m, 1H), 4.22-4.29 (m, 4H). HRMS(ESI) calcd for C28H22F2N4 [M+H]+ 453.1886, found 453.1890.

Method G Step b:2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine

Todibenzyl-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amine(1.795 g, 3.97 mmol) in methanol (100 mL) was added 20% palladiumhydroxide on carbon (646 mg). The reaction was stirred under hydrogenatmosphere for 12 hours (45 psi). The reaction was filtered to removethe catalyst, and then concentrated under reduced pressure. The crudewas purified by silica gel column chromatography eluting with methanol7% in methylene chloride to give2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (yield 56%over three steps).

HPLC (254 nm): R_(t): 3.93 min.

¹H NMR (401 MHz, DMSO-d6) δ=13.47 (br. s., 1H), 8.35-8.48 (m, 3H),7.13-7.27 (m, 2H), 6.74-6.95 (m, 2H), 5.05 (br. s., 2H). HRMS (ESI)calcd for C14H10F2N4 [M+H]+ 273.0947, found 273.0946.

Step c:N-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-benzenesulfonamide

To 2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (60 mg,0.22 mmol) in anhydrous pyridine (0.2 M) 2,5-difluoro-benzenesulfonylchloride(30 μL, 0.22 mmol) was added. The reaction was stirred at roomtemperature under nitrogen atmosphere overnight. The solvent was removedunder reduced pressure and the residue was dissolved in ethylacetate andwashed with NaHCO₃ saturated solution. The organic layer was dried overanhydrous sodium sulfate and filtered. The product was isolated bysilica gel column chromatography eluting with methanol 7% in methylenechloride (yield 70%, white solid).

¹H NMR (401 MHz, DMSO-d6) δ=13.57 (s, 1H), 10.68 (br. s., 1H), 8.45 (d,J=1.6 Hz, 1H), 8.38 (m, 2H), 7.54 (td, J=3.7, 8.2 Hz, 1H), 7.38-7.49 (m,3H), 7.20 (td, J=0.9, 8.9 Hz, 1H), 7.02 (m, 2H).

HRMS (ESI) calcd for C20H12F4N4O2S [M+H]+ 449.069, found 449.0696

Operating in an analogous way the following compounds were prepared:

Propane-1-sulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide (Cmpd.21)

[(I)C, X═CH; R1, R2, R4, R5=H; R3, R6=F; m=0; R7′=propyl]

HPLC (254 nm): R_(t): 4.59 min.

¹H NMR (401 MHz, DMSO-d6) δ=13.61 (br, s, 1H), 9.65 8 (s, 1H), 8.50 (s,1H), 8.40-8.42 (m, 2H), 7.50-7.60 (m, 1H), 7.20-7.40 (m, 1H), 7.10-7.18(m, 2H), 2.96-3.02 (m, 2H), 1.61-1.71 (m, 2H), 0.85-0.95 (m, 3H). HRMS(ESI) calcd for C17H16F2N4O2S [M+H]+ 379.1035, found 379.1039

Thiophene-3-sulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide (Cmpd.19)

[(I)C, X═CH; R1, R2, R4, R5=H; R3, R6=F; m=0; R7′=thiophen-3-yl]

HPLC (254 nm): R_(t): 4.82 min.

¹H NMR (401 MHz, DMSO-d6) δ=13.56 (s, 1H), 10.16 (br. s., 1H), 8.46 (d,J=1.7 Hz, 1H), 8.41 (d, J=6.0 Hz, 2H), 8.08 (dd, J=1.3, 3.0 Hz, 1H),7.67 (dd, J=1.3, 5.1 Hz, 1H), 7.40 (td, J=5.9, 8.8 Hz, 1H), 7.23 (dd,J=1.2, 5.1 Hz, 1H), 7.18 (td, J=1.2, 8.9 Hz, 1H), 7.04 (dd, J=1.5, 4.8Hz, 2H). HRMS (ESI) calcd for C18H12F2N4O2S [M+H]+ 419.0443, found419.0451.

Furan-2-sulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]amide (Cmpd. 20)

[(I)C, X═CH; R1, R2, R4, R5=H; R3, R6=F; m=0; R7′=furan-2-yl]

HPLC (254 nm): R_(t): 4.70 min.

¹H NMR (401 MHz, DMSO-d6) δ=13.55 (s, 1H), 10.51 (br. s., 1H), 8.44 (d,J=1.6 Hz, 1H), 8.39 (d, J=5.6 Hz, 1H), 8.11 (s, 1H), 7.87 (dd, J=0.9,1.7 Hz, 1H), 7.37 (td, J=5.8, 8.8 Hz, 1H), 7.18 (t, J=8.9 Hz, 1H), 7.03(d, J=6.1 Hz, 2H), 6.99 (d, J=3.4 Hz, 1H), 6.52 (dd, J=1.8, 3.5 Hz, 1H).HRMS (ESI) calcd for C18H12F2N4O2S [M+H]+ 403.0671, found 403.067.

2,2,2-Trifluoro-ethanesulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]amide (Cmpd. 27)

[(I)C, X═CH; R1, R2, R4, R5=H; R3, R6=F; m=0; R7′=2,2,2-trifluoroethyl]

HPLC (254 nm): R_(t): 4.78

¹H NMR (401 MHz, DMSO-d6) δ=13.62 (s, 1H), 10.36 (br. s., 1H), 8.50 (d,J=1.7 Hz, 1H), 8.40 (d, J=6.0 Hz, 2

H), 7.54-7.71 (m, 1H), 7.21-7.39 (m, 1H), 7.18 (d, J=6.1 Hz, 2H), 4.51(q, J=9.7 Hz, 2H)

HRMS (ESI) calcd for C16H11F5N4O2S [M+H]+ 419.0596, found 419.0593.

Propane-2-sulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide

[(I)C, X═CH; R1, R2, R4, R5=H; R3, R6=F; m=0; R7′=2-propyl]

HPLC (254 nm): R_(t): 4.52

¹H NMR (401 MHz, DMSO-d6) δ=13.61 (s, 1H), 9.64 (s, 1H), 8.50 (d, J=1.7Hz, 1H), 8.39-8.45 (m, 2H), 7.53-7.59 (m, 1H), 7.19-7.26 (m, 1H),7.15-7.17 (m, 2H), 3.11-3.18 (m, 1H), 1.21 (d, J=6.71 Hz, 6H).

HRMS (ESI) calcd for C17H16F2N4O2S [M+H]+ 379.1035, found 379.1034.

Cyclopropanesulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]amide (Cmpd. 26)[(I)C, X═CH; R1, R2, R4, R5=H; R3, R6=F; m=0; R7′=cyclopropyl]

HPLC (254 nm): R_(t): 4.43

¹H NMR (401 MHz, DMSO-d6) δ=13.50 (s, 1H), 9.64 (s, 1H), 8.39-8.50 (m,3H), 7.51-7.59 (m, 1H), 7.19-7.27 (m, 1H), 7.14-7.16 (m, 2H), 2.32-2.34(m, 1H), 0.82-0.86 (m, 4H).

HRMS (ESI) calcd for C17H14F2N4O2S [M+H]+ 377.0879, found 377.088.

Cyclohexanesulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide (Cmpd.29)

[(I)C, X═CH; R1, R2, R4, R5=H; R3, R6=F; m=0; R7′=cyclohexyl]

HPLC (254 nm): R_(t): 5.19

¹H NMR (401 MHz, DMSO-d6) δ=13.61 (br. s., 1H), 8.49 (d, J=1.5 Hz, 1H),8.42 (d, J=6.0 Hz, 2H), 7.56 (s, 1

H), 7.18-7.35 (m, 1H), 7.15 (d, J=6.0 Hz, 2H), 2.84 (br. s., 1H),1.96-2.08 (m, 2H), 1.69 (br. s., 2H), 1.57 (br. s., 2H), 1.32 (br. s.,2H), 0.99-1.21 (m, 3H)

HRMS (ESI) calcd for C20H20F2N4O2S [M+H]+ 419.1348, found 419.1346.

Example 231-[2,4-Difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea

[(I)E, X═CH; R1, R2, R4, R5=H; R3, R6=F; m=0; Y═H;R7=4-trifluoromethylphenyl]

Method G Step e

To 2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (70 mg,0.25 mmol) (prepared as described in Example 22) in anhydrousN,N-dimethylformamide (2.5 mL) was addedtrifluoromethyl-phenylisocyanate (35 μL, 0.25 mmol) at 0° C. Thereaction was allowed to warm to room temperature and it was stirredunder nitrogen atmosphere for two days to yield a mixture of mono- anddi-urea derivatives. Solvent was removed under reduced pressure. To thecrude of reaction in methanol (3 mL) triethylamine (138 μL, 1 mmol) wasadded and the reaction was stirred at room temperature for two hours inorder to transform the di-urea into the mono-urea derivative. Thesolvent was removed under reduced pressure and the residue was dissolvedin ethyl acetate and washed successively with NaHCO₃ saturated solution.The organic layer was dried over anhydrous sodium sulfate and filtered.The product was isolated by silica gel column chromatography elutingwith methanol 10% in methylene chloride.

HPLC (254 nm): R_(t): 6.02 min.

¹H NMR (401 MHz, DMSO-d6) δ=13.5 (s, 1H), 9.40 (s, 1 h), 8.70-8.80 (m,5H), 7.58-7.70 (m, 4H), 7.10-7.20 (m, 3H). HRMS (ESI) calcd forC22H14F5N5O [M+H]+ 460.1192, found 460.1182.

Example 24N-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2-(4-trifluoromethyl-phenyl)-acetamide

[(I)G, X═CH; R1, R2, R4, R5=H; R3, R6=F; m=0;R7=4-trifluoromethylphenylmethyl]

Method G Step h

To (4-trifluoromethyl-phenyl)-acetic acid (49 mg, 0.24 mmol) inanhydrous tetrahydrofuran (3 mL)1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (63 mg, 0.24mmol) was added, after 10 minutes 1-hydroxybenzotriazole (38 mg, 0.28mmol) and after 30 minutes2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine (60 mg, 0.22mmol) (prepared as described in Example 22) were added. The reaction wasstirred under nitrogen atmosphere at room temperature overnight to yielda mixture of mono- and bis-amide (3:1 ratio at 254 nm). The reaction wasconcentrated under reduced pressure and the residue was dissolved inethyl acetate, washed successively with NaHCO₃ saturated solution andthe organic layer was dried over anhydrous sodium sulfate and filtered.The monoamide derivative was isolated by silica gel columnchromatography eluting with ethanol 7% in methylene chloride.

HPLC (254 nm): R_(t): 5.76 min.

¹H NMR (401 MHz, DMSO-d6) δ=13.59 (br. s., 1H), 10.07 (br. s., 1H), 8.49(s, 1H), 8.40-8.45 (m, 2H), 7.90-7.98 (m, 1H), 7.68 (d, J=8.1 Hz, 2H),7.54 (d, J=8.1 Hz, 2H), 7.09-7.25 (m, 3H), 3.83 (s, 2H). HRMS (ESI)calcd for C23H15F5N40 [M+H]+ 459.1239, found 459.1243.

Example 25N-[3-(1-Ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide(Cmpd. 51)

[(I)C, X═CH; R1, R2, R4, R5=H; R3, R6=F; m=2; R7′=2,5-difluoro-phenyl]

Method A Step hDibenzyl-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-amine

Dibenzyl-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amine(prepared as described in Example 22) (4 g, 8.84 mmol) was suspended inDCM (44 mL) and 32% NaOH (44 mL) was added followed bytetrabutylammonium bromide (400 mg, 1.24 mmol, 0.14 eq). Neatethyliodide (1.07 mL, 13.27 mmol, 1.5 eq) was then added and thebiphasic mixture was vigorously stirred at room temperature for 1 h. ByHPLC analysis at 254 nm the regioisomeric ratio was 55:45 in favour ofthe most polar N1-substituted pyrazole. The reaction mixture was thendiluted with water (50 mL) and DCM (50 mL) and the two layers wereseparated. Aqueous phase was extracted with DCM (2×50 mL) and combinedorganic layers were washed with water (2×50 mL) and brine (50 mL), driedover Na₂SO₄ and evaporated to dryness. The two reagioisomers wereseparated by flash chromatography on silica gel (n-hexane/ethyl acetate1:1) and the desired N¹-ethylpyrazole was obtained as a white solid in52% yield.

HPLC (254 nm): R_(t): 7.38 min.

¹H-NMR (401 MHz, DMSO-d6) δ=8.47 (s, 1H), 8.37 (d, J=6.0 Hz, 2H),7.20-7.33 (m, 10H), 7.03-7.10 (m, 3H), 6.89-6.97 (m, 1H), 4.18-4.30 (m,6H), 1.47 (t, J=7.3 Hz, 3H). HRMS (ESI) calcd for C30H26F2N4 [M+H]⁺481.2199, found 481.2197.

Method G Step b3-(1-Ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenylamine

Dibenzyl-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-amine(2.35 g, 4.89 mmol) was dissolved in methanol (140 mL). 20% Palladiumhydroxide on carbon (500 mg) was added and the reaction was stirredunder hydrogen atmosphere (50 psi) for 7 h. A further addition ofcatalyst was made (500 mg) and hydrogenation was continued for 6 morehours. The reaction mixture was filtered over a Celite pad and thenconcentrated under reduced pressure. The crude product was purified byflash chromatography on silica gel (DCM/methanol 95:5) to give 1.16 g ofthe desired product as a colourless foam (79% yield).

HPLC (254 nm): R_(t): 4.56 min.

¹H-NMR (401 MHz, DMSO-d6) δ=8.46 (s, 1H), 8.39-8.43 (m, 2H), 7.11-7.18(m, 2H), 6.81-6.93 (m, 2H), 5.05 (s, 2H), 4.23 (q, J=7.3 Hz, 2H), 1.46(t, J=7.3 Hz, 3H). HRMS (ESI) calcd for C16H14F2N4 [M+H]+ 301.1260,found 301.1251.

Step bN-[3-(1-Ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide

3-(1-Ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenylamine(1.146 g, 3.816 mmol) was dissolved in anhydrous pyridine (30 M) undernitrogen atmosphere and cooled to 0° C. 2,5-Difluoro-benzenesulfonylchloride (0.513 mL, 3.816 mmol, 1 eq) was added and the mixture wasallowed to stir at the same temperature. Further additions of sulfonylchloride (for a total amount of 0.650 mL) were needed to drive thereaction to completion. The reaction mixture was kept at 0° C. overnightand then it was allowed to reach room temperature. The solvent wasremoved under reduced pressure and the residue was dissolved in ethylacetate and washed with NaHCO₃ saturated aqueous solution. The organiclayer was dried over anhydrous sodium sulfate and evaporated to dryness.The crude product was slurried in methanol at 50° C. for 10 minutes andthe solid was filtered and washed with ethyl ether. After drying at 40°C. for 5 hours 1.13 g of the title compound were obtained as a whitesolid (62% yield).

HPLC (254 nm): R_(t): 5.68 min.

¹H-NMR (401 MHz, DMSO-d6) δ=10.68 (br. s., 1H), 8.45 (s, 1H), 8.38 (d,J=6.0 Hz, 2H), 7.50-7.58 (m, 1H), 7.40-7.49 (m, 3H), 7.15-7.23 (m, 1H),6.96-7.02 (m, 2H), 4.22 (q, J=7.2 Hz, 4H), 1.44 (t, J=7.3 Hz, 3H).

HRMS (ESI) calcd for C22H16F4N4O2S [M+H]+ 477.1003, found 477.0997.

Operating in an analogous way the following compounds were obtained:

N-[3-(1-Ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide(Cmpd. 57)

[(I)C, X═CH; R1, R2, R4, R5=H; R3, R6=F; m=2; R7′=2-fluoro-phenyl]

HPLC (254 nm): R_(t): 5.53 min.

¹H-NMR (401 MHz, DMSO-d6) δ=10.49 (s, 1H), 8.44 (s, 1H), 8.37-8.40 (m,2H), 7.59-7.73 (m, 2H), 7.42 (td, J. 6.0, 8.9 Hz, 1H), 7.28-7.38 (m,2H), 7.14-7.21 (m, 1H), 6.92-6.98 (m, 2H), 4.14-4.27 (m, 2H), 1.44 (t,J=7.3 Hz, 3H).

HRMS (ESI) calcd for C22H18F3N4O2S [M+H]+ 459.1097, found 459.1091.

Operating in an analogous way the following compounds were obtained:

N-[3-(1-Ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide(Cmpd. 58)

[(I)C, X═CH; R1, R2, R4, R5=H; R3, R6=F; m=2; R7′=3-fluoro-phenyl]

HPLC (254 nm): R_(t): 5.67 min.

¹H-NMR (401 MHz, DMSO-d6) δ=10.38 (s, 1H), 8.44 (s, 1H), 8.35-8.42 (m,2H), 7.44-7.62 (m, 4H), 7.40 (td, J. 5.9, 8.9 Hz, 1H), 7.18 (td, J=1.5,8.9 Hz, 1H), 6.98 (d, J=6.1 Hz, 2H), 4.21 (q, J=7.3 Hz, 2H), 1.44 (t,J=7.3 Hz, 3H).

HRMS (ESI) calcd for C22H18F3N4O2S [M+H]+ 459.1097, found 459.1100.

Example 26N-{2,4-Difluoro-3-[4-(2-methylamino-pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}-2,5-difluoro-benzenesulfonamide)(Cmpd. n^(o) 53)

[(I)C, X═CH; R1, R4, R5=H; R2=methylamino; R3, R6=F; m=2;R7′=2,5-difluoro-phenyl]

Method A Step e1-(3-Dibenzylamino-2,6-difluoro-phenyl)-2-(2-fluoro-pyridin-4-yl)-ethanone

To a solution of 2-fluoro-4-methyl-pyridine (5.76 mL, 0.056 mol) inanhydrous tetrahydrofuran (200 mL) at 0° C. sodium hexamethyldisilazide(NaHMDS, 2 M in tetrahydrofuran, 36 mL, 0112 mol) was added and thereaction was stirred for 1 hour. A solution of3-dibenzylamino-2,6-difluoro-benzoic acid benzyl ester (25 g, 0.056 mol)in tetrahydrofuran (80 mL) was then added dropwise to the reactionmixture, which was stirred at 0° C. for one hour and allowed to warm atroom temperature. The reaction mixture was then poured into saturatedaqueous ammonium chloride and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The crude was purifiedby silica gel column chromatography eluting with ethyl acetate 15% inhexane (40.7%).

HPLC (254 nm): R_(t): 7.89

¹H-NMR (401 MHz, DMSO-d6) δ=8.19 (d, J=5.1 Hz, 1H), 7.09 (s, 1H),7.02-7.17 (m, 2H), 6.93-7.02 (m, 1H), 4.40 (s, 2H), 4.25-4.29 (m, 4H).

HRMS (ESI) calcd for C13H9F3N2O [M+H]+ 447.1679, found 447.1666.

Step f(E)-1-(3-Dibenzylamino-2,6-difluoro-phenyl)-3-dimethylamino-2-(2-fluoro-pyridin-4-yl)-propenone

To1-(3-Dibenzylamino-2,6-difluoro-phenyl)-2-(2-fluoro-pyridin-4-yl)-ethanone(5 g, 0.01 mol) in toluene (100 mL) was addeddimethoxymethyl-dimethyl-amine (6 mL, 0.04 mol). The reaction wasstirred at 80° C. for one hour and the solvent was concentrated underreduced pressure. The crude was used in the next step without furtherpurification.

Step g1Dibenzyl-{2,4-difluoro-3-[4-(2-fluoro-pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}-amine

To(E)-1-(3-Dibenzylamino-2,6-difluoro-phenyl)-3-dimethylamino-2-(2-fluoro-pyridin-4-yl)-propenone(5.6 g, 0.01 mol) was added hydrazine in tetrahydrofuran 1M (40 mL, 0.04mol). The reaction mixture was stirred under nitrogen atmosphere at 70°C. for one hour. The reaction was concentrated under reduced pressureand the crude was used in the next step without further purification.

HPLC (254 nm): R_(t): 7.3

¹H-NMR (401 MHz, DMSO-d6) δ=13.64 (br. s., 1H), 8.58 (d, J=1.7 Hz, 1H),8.04 (d, J=5.2 Hz, 1H), 6.89 (s, 1

H), 6.85-7.35 (m, 13H), 4.15-4.32 (m, 4H)

HRMS (ESI) calcd for C28H21F3N4 [M+H]+ 471.1791, found 447.1795.

Method E Step b1{4-[3-(3-Dibenzylamino-2,6-difluoro-phenyl)-1H-pyrazol-4-yl]-pyridin-2-yl}-methyl-amine

To a solution ofdibenzyl-{2,4-difluoro-3-[4-(2-fluoro-pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}-amine(400 mg, 0.849 mmol) in DMSO (4.24 mL), a 40% methyl amine solution inwater (3.5 mL) was added. The mixture was irradiated in the microwaveoven at 120° C. for one hour and then poured into water and extractedwith ethyl acetate. The organic layer was washed three times withsaturated aqueous NaHCO₃ and once with brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated under reducepressure and the crude product was used in the following step withoutfurther purification.

HPLC (254 nm): R_(t): 6.66

¹H-NMR (401 MHz, DMSO-d6) δ=13.39 (br. s., 1H), 8.27 (s, 1H), 7.78 (d,J=5.5 Hz, 1H), 7.16-7.33 (m, 12H), 6.17-6.30 (m, 3H), 4.22 (s, 4H), 2.58(d, J=4.4 Hz, 3H). HRMS (ESI) calcd for C29H25F2N5 [M+H]+ 482.2151,found 482.2149.

Method G Step b{4-[3-(3-Amino-2,6-difluoro-phenyl)-1H-pyrazol-4-yl]-pyridin-2-yl}-methyl-amine

To a solution of{4-[3-(3-dibenzylamino-2,6-difluoro-phenyl)-1H-pyrazol-4-yl]-pyridin-2-yl}-methyl-amine(408 mg, 0.849 mmol) in toluene (4.30 mL) trifluoro-methanesulfonic acid(4.30 mL) was added and the mixture was irradiated in the microwave ovenat 120° C. for 30 minutes. The reaction was then poured into water andextracted with ethyl acetate. The organic layer was washed withsaturated aqueous NaHCO₃ and brine, dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated under reduced pressure andpurified by silica gel column chromatography eluting with 5% methanol inmethylene chloride (60% over 4 steps).

HPLC (254 nm): R_(t): 3.37

¹H-NMR (401 MHz, DMSO-d6) δ=13.31 (s, 1H), 8.15 (s, 1H), 7.80 (d, J=5.37Hz, 1H), 6.79-6.98 (m, 2H), 6.34-6.36 (m, 1H), 6.27 (br. s, 1H), 6.21(br. s, 1H), 5.00 (br.s., 2H), 2.60-2.68 (m, 3H).

HRMS (ESI) calcd for C15H13F2N5 [M+H]+ 302.1212, found 302.1206.

Step cN-{2,4-Difluoro-3-[4-(2-methylamino-pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}-2,5-difluoro-benzenesulfonamide

To a solution of{4-[3-(3-amino-2,6-difluoro-phenyl)-1H-pyrazol-4-yl]-pyridin-2-yl}-methyl-amine(144 mg, 0.48 mmol) in anhydrous pyridine (0.2 M),2,5-difluoro-benzenesulfonyl chloride (64 μL, 0.48 mmol) was added andthe reaction mixture was stirred at room temperature under nitrogenatmosphere overnight. The solvent was removed under reduced pressure andthe residue was dissolved in ethyl acetate and washed with saturatedaqueous NaHCO₃. The organic layer was dried over anhydrous sodiumsulfate and filtered. The product was isolated by silica gel columnchromatography eluting with methanol 5% in methylene chloride (58%).

HPLC (254 nm): R_(t): 4.73

¹H-NMR (401 MHz, DMSO-d6) δ=13.42 (s, 1H), 10.73 (br. S, 1H), 8.26 (d,J=1.47, 1H), 7.75-7.79 (m, 1H), 7.10-7.59 (m, 5H), 6.10-6.40 (m, 3H),2.60-2.70 (m, 3H). HRMS (ESI) calcd for C21H15F4N5O2S [M+H]⁺ 478.0956,found 478.0947.

Operating in an analogous way the following ethylaminopyridine analogwas prepared:

N-{3-[4-(2-Ethylamino-pyridin-4-yl)-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide

(Cmpd. n^(o) 54) [(I)C, X═CH; R1, R4, R5=H; R2=ethylamino; R3, R6=F;m=2; R7′=2,5-difluoro-phenyl]

HPLC (254 nm): R_(t): 5.04

¹H-NMR (401 MHz, DMSO-d6) δ=1H NMR (401 MHz, DMSO-d6)=13.42 (s, 1H),10.74 (br. s., 1H), 8.25 (br. s, 1H), 7.74-7.78 (m, 1H), 7.10-7.60 (m,5H), 6.08-6.40 (m, 3H), 3.04-3.18 (m, 2H), 1.00-1.07 (t, J=7.20 Hz, 3H).

HRMS (ESI) calcd for C22H17F4N5O2S [M+H]+ 492.1112, found 492.11

Example 27N-(4-{3-[3-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-1H-pyrazol-4-yl}pyridin-2-yl)propanamide

(Cmpd. n^(o) 39) [(I)V, R1, R3, R4, R5, R6=H; m=0; A=NHCONH;R7=4-trifluoromethylphenyl; R16=ethyl]

Method C Step a (2E)-3-(dimethylamino)-1-(3-nitrophenyl)prop-2-en-1-one

5 g (30 mmol) of 3-nitro-acetophenone were dissolved in 20 ml of drytetrahydrofuran and 5 ml (38 mmol) of dimethylformamide dimethylacetalwere added. The mixture was stirred at 65° C. for 3 hours, then thesolvent removed under reduced pressure. The crude was triturated withdiisopropylether and collected by filtration, giving 6.5 g of the titlecompound.

¹H NMR (401 MHz, DMSO-d6) δ ppm 2.97 (s, 3H) 3.19 (s, 3H) 5.91 (d,J=12.08 Hz, 1H) 7.74 (t, J=8.00 Hz, 1H) 7.83 (d, J=11.96 Hz, 1H)8.30-8.37 (m, 2H) 8.61 (t, J=1.89 Hz, 1H).

HRMS (ESI): calcd for C11H12N2O3 [M+H]+ 221.0921 found 221.0915

Step b 3-(3-nitrophenyl)-1H-pyrazole

2.5 g (11 mmol) of(2E)-3-(dimethylamino)-1-(3-nitrophenyl)prop-2-en-1-one were dissolvedin 25 ml of ethanol and 2.3 ml of hydrazine hydrate 98% (46 mmol) wereadded. The resulting solution was refluxed under stirring for 5 hours.The solvent was then evaporated and the crude was dissolved withdichloromethane and washed with water. The organic layer was dried oversodium sulphate and the solvent removed in vacuo. The residue was thentriturated with diisopropylether and collected by filtration, giving 2.1g of the title compound (98%).

¹H NMR (401 MHz, DMSO-d6) δ ppm 6.93 (d, J=2.32 Hz, 1H) 7.71 (t, J=7.99Hz, 1H) 7.86 (br. s., 1H) 8.14 (d, J=8.18 Hz, 1H) 8.26 (d, J=7.32 Hz,1H) 8.61 (t, J=1.89 Hz, 1H) 13.12 (br. s., 1H).

MS (ESI) (−) 188 m/z [M−H]−; 248 m/z [M+AcOH—H]−

Step c 4-iodo-3-(3-nitrophenyl)-1H-pyrazole

2.1 g (11 mmol) of 3-(3-nitrophenyl)-1H-pyrazole were dissolved in 25 mlof dry dimethylformamide and 2.63 g (11.7 mmol) of N-iodosuccinimidewere added. After 5 hours under stirring at 70° C. the most part ofsolvent was removed in vacuo and an aqueous solution of sodiumthiosulphate was added and the product extracted several times withdichloromethane. The organic phase was then dried over sodium sulphateand evaporated to give, after trituration with diisopropylether, 2.6 g(74%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) δ ppm 7.79 (t, J=7.99 Hz, 1H) 8.08 (br. s.,1H) 8.21-8.33 (m, 2H) 8.68 (s, 1H) 13.62 (br. s., 1H).

MS (ESI) (−) 314 m/z [M−H].

Step d 4-iodo-1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazole

2 g (6.3 mmol) of 4-iodo-3-(3-nitrophenyl)-1H-pyrazole were dissolved in20 ml of dry dimethylformamide and 2.46 g (7.5 mmol) of cesium carbonateand 0.85 ml (6.3 mmol) of p-methoxybenzyl chloride were addedsuccessively. The reaction mixture was heated at 70° C. under stirringfor 5 hours. Water was then added and the product extracted withdichloromethane. The organic phase was dried over sodium sulphate andthe solvent evaporated under reduced pressure. 2.4 g (86%) of the titlecompound crystallized from a mixture diethylether-diisopropylether.

¹H NMR (401 MHz, DMSO-d6) δ ppm 3.73 (s, 3H) 5.32 (s, 2H) 6.90-6.95 (m,2H) 7.27-7.34 (m, 2H) 7.76 (t, J=8.06 Hz, 1H) 8.16 (s, 1H) 8.23 (ddd,J=8.24, 2.38, 0.98 Hz, 1H) 8.27 (ddd, J=7.75, 1.65, 1.10 Hz, 1H) 8.64(t, J=1.89 Hz, 1H).

HRMS (ESI): calcd for C17H141N303[M+H]+ 436.0153 found 436.0166.

Step h 4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine

To a solution of 100 mg (0.23 mol) of4-iodo-1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazole in 16 ml ofdioxane and 4 ml of water, 90 mg (0.46 mmol) of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 52 mg (0.046mmol) of palladium tetrakis and 150 mg (0.46 mmol) mg of cesiumcarbonate were added successively. The mixture was submitted tomicrowave irradiation at 120° C. for 30 minutes in a sealed vial. Thereaction was filtered through a celite pad and the solvent evaporated todryness. The crude was then partitioned between dichloromethane andwater, the organic layer dried over sodium sulphate and the solventremoved in vacuo. After purification by flash-chromatography on a silicagel column (CH₂Cl₂-CH₃COCH₃) 78 mg (88%) of the title compound wereobtained.

¹H NMR (401 MHz, DMSO-d6) δ ppm 3.74 (s, 3H) 5.36 (s, 2H) 6.91-6.98 (m,2H) 7.24-7.27 (m, 2H) 7.34-7.39 (m, 2H) 7.60-7.65 (m, 1H) 7.80 (ddd,J=7.87, 1.34, 1.16 Hz, 1H) 8.19-8.21 (m, 1H) 8.21-8.23 (m, 1H) 8.34 (s,1H) 8.48-8.51 (m, 2H).

HRMS (ESI): calcd for C22H18N403[M+H]+ 387.1452 found 387.1452.

Method E Step a4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine1-oxide

100 mg (0.26 mmol) of4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-pyridine weredissolved in 3 mL of dichloromethane and 80 mg (0.52 mmol) ofm-chloroperbenzoic acid were added. The mixture was stirred at roomtemperature for 4 hours, diluted with the same solvent and washed withaqueous sodium hydrogenocarbonate. The organic layer was then dried oversodium sulphate and evaporated to afford, after crystallization fromethylacetate, 49 mg (47%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) δ ppm 3.74 (s, 3H) 5.35 (s, 2H) 6.88-6.98 (m,2H) 7.22-7.29 (m, 2H) 7.33-7.39 (m, 2H) 7.64-7.71 (m, 1H) 7.83 (ddd,J=7.93, 1.34, 1.10 Hz, 1H) 8.10-8.17 (m, 2H) 8.19-8.24 (m, 2H) 8.31 (s,1H).

HRMS (ESI): calcd for C22H18N4O4 [M+H]+ 403.1401 found 403.1415.

Step cN-tert-butyl-4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridin-2-amine

580 mg (1.44 mmol) of4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine1-oxide were suspended in a mixture of 16 ml of trifluoromethylbenzeneand 4 ml of dry dichloromethane and 756 μl of tert-butylamine wereadded. At 0° C. 936 mg (7.2 mmol) of p-toluensulfonic anhydride wereadded. After 6 hours under stirring in the same conditions the solventwas removed under reduced pressure, the residue partitioned betweendichloromethane and water, the organic layer dried over sodium sulphateand evaporated. The crude was then purified by flash-chromatography on asilica gel column (CH2Cl2-CH3COCH3 19/1), giving 500 mg (75%) of thetitle compound.

¹H NMR (401 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 3.74 (s, 3H) 5.34 (s, 2H)6.09 (s, 1H) 6.27 (dd, J=5.31, 1.40 Hz, 1H) 6.39 (dd, J=1.28, 0.67 Hz,1H) 6.94 (d, J=8.79 Hz, 2H) 7.35 (d, J=8.67 Hz, 2H) 7.66 (t, J=7.99 Hz,1H) 7.84 (ddd, J=7.69, 1.46, 1.10 Hz, 1H) 7.88 (dd, J=5.25, 0.49 Hz, 1H)8.09 (s, 1H) 8.18 (ddd, J=8.27, 2.35, 0.98 Hz, 1H) 8.27 (t, J=1.83 Hz,1H).

HRMS (ESI): calcd for C26H27N503[M+H]+ 458.2187 found 458.2190.

Method G Step a4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-tert-butylpyridin-2-amine

400 mg (0.87 mmol) ofN-tert-butyl-4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridin-2-aminewere dissolved in 15 ml of dioxane and 4 ml of water and 227 mg (3.48mmol) of metallic zinc and 461 (8.7 mmol) of ammonium chloride wereadded. The mixture was stirred at 100° C. for 4 hours, then filteredthrough a celite pad. The filtrate was evaporated and the residuepartitioned between dichloromethane and aqueous sodiumhydrogenocarbonate. The organic phase was then dried and evaporated andthe residue purified by flash-chromatography on a silica gel column(CH2Cl₂-CH3COCH3 from 9/1 to 7/3), giving 180 mg (48%) of the titlecompound.

HRMS (ESI): calcd for C26H29N5O [M+H]+ 428.2445 found 428.2452.

Step e1-(3-{4-[2-(tert-butylamino)pyridin-4-yl]-1-(4-methoxybenzyl)-1H-pyrazol-3-yl}phenyl)-3-[4-(trifluoromethyl)phenyl]urea

350 mg (0.82 mmol) of4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-tert-butyl-pyridin-2-aminewere dissolved in 30 ml of dry dimethylformamide and 110 μl (0.82 mmol)of p-trifluoromethyl-phenyl isocyanate were added to the resultingsolution. The mixture was stirred overnight at room temperature, thenpoured into an aqueous solution of sodium hydrogenocarbonate andextracted with dichloromethane. The organic phase was dried over sodiumsulphate and evaporated in vacuo. The residue was chromatographed on asilica gel column (dichloromethane-acetone 9/1), affording 302 mg (60%)of the title compound.

¹H NMR (401 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 3.75 (s, 3H) 5.31 (s, 2H)6.02 (s, 1H) 6.26 (dd, J=5.30, 1.40 Hz, 1H) 6.42 (d, J=0.61 Hz, 1H)6.88-6.97 (m, 2H) 7.00 (ddd, J=7.86, 1.28, 1.10 Hz, 1H) 7.27 (t, J=7.87Hz, 1H) 7.31-7.36 (m, 2H) 7.47-7.51 (m, 1H) 7.55 (t, J=1.77 Hz, 1H)7.58-7.69 (m, 4H) 7.84 (d, J=5.24 Hz, 1H) 8.01 (s, 1H) 8.84 (s, 1H) 9.01(s, 1H).

HRMS (ESI): calcd for C34H33F3N6O2 [M+H]+ 615.2690 found 615.2687.

Method K Step d1-{3-[4-(2-aminopyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)phenyl]urea

100 mg (0.16 mmol) of1-(3-{4-[2-(tert-butylamino)pyridin-4-yl]-1-(4-methoxybenzyl)-1H-pyrazol-3-yl}phenyl)-3-[4-(trifluoromethyl)phenyl]ureawere dissolved with 5 ml of trifluoroacetic acid and the solutionstirred at 70° C. for 6 hours. The mixture was then poured into icywater, neutralized with aqueous sodium hydrogenocarbonate and extractedwith ethylacetate. The organic layer was dried over sodium sulphate andevaporated to dryness. The residue was purified by flash-chromatographyon a silica gel column (dichloromethane-methanol, from 1% to 10%),giving 63 mg (90%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) (mixture of tautomers) δ ppm 5.83 (br. s., 2H)6.38 (dd, J=5.30, 1.40 Hz, 1H) 6.41 (br. s., 1H) 7.05 (d, J=7.19 Hz, 1H)7.29-8.02 (many br signals, 4H) 7.60-7.68 (m, 4H) 7.80 (d, J=5.37 Hz,1H) 8.80-8.98 (m, 1H) 9.10 (br.s., 1H) 13.28 and 13.15 (2 br.s., 1H).

HRMS (ESI): calcd for C22H17F3N5O [M+H]+ 439.1489 found 439.1490.

Step eN-(4-{3-[3-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-1H-pyrazol-4-yl}pyridin-2-yl)propanamide

35 mg (0.08 mmol) of1-{3-[4-(2-aminopyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)-phenyl]ureawere dissolved in 2 ml of dry tetrahydrofuran and 27 μl (0.16 mmol) ofN,N-diisopropylethylamine and 14 μl of propionyl chloride (0.16 mmol)were added consecutively. The mixture was stirred overnight at roomtemperature, then poured into aqueous sodium hydrogenocarbonate,extracted with dichloromethane, dried over sodium sulphate edevaporated. Without any further purification the crude was redissolvedwith 10 mL of methanol and 5 mL of triethylamine were added. After 7hours at room temperature the solvent was removed in vacuo, the residuepartitioned between dichloromethane and water, dried over sodiumsulphate and evaporated. After trituration with diethylether, 30 mg(77%) of the title compound were collected by filtration.

¹H NMR (401 MHz, DMSO-d6) (mixture of tautomers) δ=1.03 (t, J=7.6, 3H),2.31-2.41 (q, J=7.6, 2H), 6.85-6.91 (m, 1H), 7.00-7.09 (m, 1H),7.23-7.56 (3 m, 3H), 7.59-7.67 (m, 4H), 8.09-8.18 (m, 2H), 8.15 (d,J=5.3, 1H), 8.73-8.91 (m, 1H), 8.97-9.11 (m, 1H), 10.33 (s, 1H), 13.38and 13.25 (2 br. s., 1H). HRMS (ESI): calcd for C25H21F3N6O2 [M+H]+495.1751 found 495.1746.

Operating in an analogous way the following compounds were obtained:

2-methyl-N-(4-{3-[3-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-1H-pyrazol-4-yl}pyridin-2-yl)propanamide(Cmpd. n^(o) 40)

[(I)V, R1, R3, R4, R5, R6=H; m=0; A=NHCONH; R7=4-trifluoromethylphenyl;R16=isopropyl]

¹H NMR (401 MHz, DMSO-d6) δ=1.03-1.08 (m, 6H) 2.67-2.79 (m, 1H)6.83-6.89 (m, 1H) 6.99-7.08 (m, 1H) 7.20-7.57 (m, 3H) 7.58-7.67 (m, 4H)7.81 (br.s., 1H) 8.10-8.21 (m, 3H) 8.80 (br. s, 1H) 9.04 (br. s, 1H)10.33 (s, 1H).

HRMS (ESI): calcd for C26H24F3N6O2 [M+H]+ 509.1908 found 509.1896.

Example 284-hydroxy-N-(4-{3-[3-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-1H-pyrazol-4-yl}pyridin-2-yl)butanamide(Cpd. n^(o) 43)

[(I)V, R1, R3, R4, R5, R6=H; m=0; A=NHCONH; R7=4-trifluoromethylphenyl;R16=3-hydroxypropyl]

Method K Step e

30 mg (0.068 mmol) of1-{3-[4-(2-aminopyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)phenyl]ureawere dissolved in 2 ml of dry tetrahydrofuran and 15 μl (0.34 mmol) ofγ-butyrolactone were added. The reaction mixture was cooled to 0° C. anda solution of 680 μl (0.68 mmol) of hexamethyldisilazane sodium salt 1Min THF in 2 ml of the same solvent were added dropwise. The mixture wasmaintained at 0° C. for 6 hours and at room temperature overnight, thenpartitioned between dichloromethane and water. The organic phase wasdried over sodium sulphate and evaporated. The crude was finallypurified by preparative HPLC in reverse phase conditions (basic eluant),giving 20 mg (59%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) (mixture of tautomers) δ=13.39-13.25 (2br.s.,1H), 10.34 (s, 1H); 9.05 (m, 1H), 8.81 (m, 1H), 8.13-8.18 (m, 2H), 8.13and 7.82 (2bs, 1H), 7.58-7.68 (m, 4H), 7.22-7.56 (3 m, 3H) 7.04 (m, 1H),6.85 (m, 1H), 4.45 (t, J=5.4 Hz, 1H), 3.39 (m, 2H), 2.39 (t, J=7.45 Hz,2H), 1.69 (tt, J=6.59, 6.59 Hz, 2H).

HRMS (ESI): calcd for C26H24F3N603[M+H]+ 525.1857 found 525.1856.

Example 291-(3-{4-[2-(methylamino)pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-3-[4-(trifluoromethyl)phenyl]urea

[(I)E, X═CH; R1, R3, R4, R5, R6=H; m=0; R2=methylamino; Y═H;R7=4-trifluoromethylphenyl]

Method C Step h2-fluoro-4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine

1 g (2.3 mmol) of4-iodo-1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazole (prepared asdescribed in Example 27) were dissolved in a mixture of 20 ml of dioxaneand 5 ml of water in a nitrogen atmosphere. 750 mg (2.3 mmol) of cesiumcarbonate, 350 mg (0.3 mmol) of palladium tetrakis and 486 mg (3.45mmol) of 2-fluoro-pyridyl boronic acid were added and the reactionstirred at 100° C. for 4 hours. The mixture was then filtered through acelite pad and the filtrate evaporated under reduced pressure. Theresidue was re-dissolved with dichloromethane and washed with water. Theorganic layer was dried over sodium sulphate and evaporated. 680 mg(73%) of the title compound crystallized from diethylether.

¹H NMR (401 MHz, DMSO-d6) δ=3.74 (s, 3H) 5.36 (s, 2H) 6.91-6.99 (m, 2H)7.16-7.18 (m, 1H) 7.34-7.39 (m, 2H) 7.45-7.48 (m, 1H) 7.68 (dd, J=8.79,7.81 Hz, 1H) 7.78-7.83 (m, 1H) 8.15 (d, J=5.25 Hz, 1H) 8.20-8.28 (m, 2H)8.43 (s, 1H).

HRMS (ESI): calcd for C22H18FN403[M+H]+ 405.1358 found 405.1369.

Method E Step c14-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-N-methylpyridin-2-amine

500 mg (1.24 mmol) of2-fluoro-4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridinewere dissolved in a mixture of 6 ml of methylamine 40% in water and 12ml of dioxane and the mixture submitted to microwave irradiation at 130°C. for 2 hours in a sealed vial. The solvent was the removed underreduced pressure and the residue taken up with dichloromethane andwashed with water. The organic layer was dried over sodium sulphate andevaporated. The crude was finally purified by flash-chromatography on asilica gel column (CH2Cl₂-CH3COCH3 9/1), giving 300 mg (58%) of thetitle compound.

¹H NMR (401 MHz, DMSO-d6) δ=2.70 (d, J=4.88 Hz, 3H) 3.74 (s, 3H) 5.34(s, 2H) 6.29-6.31 (m, 1H) 6.34 (dd, J=5.25, 1.46 Hz, 1H) 6.40 (q, J=4.60Hz, 1H) 6.85-6.97 (m, 2H) 7.33-7.38 (m, 2H) 7.65 (t, J=8.06, 1H) 7.83(dt, J=1.2, 8.1 Hz, 1H), 7.90 (d, J=5.25 Hz, 1H) 8.17 (s, 1H) 8.16-8.21(m, 1H) 8.27 (t, J=1.89 Hz, 1H).

HRMS (ESI): calcd for C23H21N503[M+H]+ 416.1717 found 416.1720.

Operating in an analogous way the following intermediates were obtained:

N-ethyl-4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridin-2-amine

¹H NMR (401 MHz, DMSO-d6) δ=1.07 (t, J=7.14 Hz, 3H) 3.13-3.23 (m, 2H)3.74 (s, 3H) 5.34 (s, 2H) 6.29-6.35 (m, 2H) 6.44 (br.s., 1H) 6.90-6.98(m, 2H) 7.32-7.38 (m, 2H) 7.64 (t, J=8.05, 1H) 7.84 (dt, J=7.90, 1.24Hz, 1H) 7.89 (d, J=5.25 Hz, 1H) 8.17 (s, 1H) 8.17-8.21 (m, 1H) 8.26 (t,J=1.89 Hz, 1H).

HRMS (ESI): calcd for C24H23N503[M+H]+ 430.1874 found 430.1877.

N′-{4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridin-2-yl}-N,N-dimethylethane-1,2-diamine

¹H NMR (401 MHz, DMSO-d6) δ=2.23 (bs, 6H) 2.45 (bs, 2H) 3.31 (bs, 2H)3.74 (s, 3H) 5.34 (s, 2H) 6.32-6.38 (m, 3H) 6.89-6.96 (m, 2H) 7.30-7.39(m, 2H) 7.62-7.68 (m, 1H) 7.84 (dt, J=7.96, 1.21 Hz, 1H) 7.90 (m, J=5.86Hz, 1H) 8.16 (s, 1H) 8.19 (ddd, J=8.21, 2.35, 1.04 Hz, 1H) 8.25 (t,J=1.89 Hz, 1H).

HRMS (ESI): calcd for C26H28N603[M+H]+ 473.2296 found 473.2304.

4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-N-(2-methoxyethyl)pyridin-2-amine

HRMS (ESI): calcd for C25H25N504[M+H]+ 460.1980 found 460.1964.

Method G Step a

4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-methylpyridin-2-amine

300 mg (0.72 mmol) of4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-N-methylpyridin-2-aminewere dissolved in a mixture of 20 ml of dioxane and 4 ml of water and381 mg (7.2 mmol) of ammonium chloride and 190 mg (2.9 mmol) of metalliczinc were added. The reaction was maintained at 100° C. under stirringfor 6 hours. The mixture was then filtered through a celite pad and thesolvent removed in vacuo. The residue was partitioned betweendichloromethane and water, dried over sodium sulphate and evaporatedagain, giving, after trituration with diethylether, 260 mg (93%) of thetitle compound.

¹H NMR (401 MHz, DMSO-d6) δ=2.68 (d, J=4.76 Hz, 3H) 3.74 (s, 3H) 5.04(bs, 2H) 5.26 (s, 2H) 6.24-6.31 (m, 1H) 6.30 (s, 1H) 6.33 (dd, J=5.37,1.46 Hz, 1H) 6.44-6.53 (m, 2H) 6.70 (t, J=1.83 Hz, 1H) 6.90-6.94 (m, 2H)6.94-6.98 (m, 1H) 7.27-7.32 (m, 2H) 7.83 (dd, J=5.31, 0.43 Hz, 1H) 8.05(s, 1H).

HRMS (ESI): calcd for C23H23N5O [M+H]+ 386.1986 found 386.1991.

Operating in an analogous way the following intermediates were obtained:

4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-methylpyridin-2-amine

Yield 77%.

¹H NMR (401 MHz, DMSO-d6) δ=1.03-1.10 (m, 3H) 3.09-3.21 (m, 2H) 3.74 (s,3H) 5.04 (s, 2H) 5.26 (s, 2H) 6.27 (t, J=5.43 Hz, 1H) 6.32 (d, J=1.46Hz, 1H) 6.30 (s, 1H) 6.47 (dt, J=8.88, 1.30 Hz, 1H) 6.49-6.52 (m, 1H)6.70 (t, J=1.89 Hz, 1H) 6.90-7.00 (m, 3H) 7.24-7.35 (m, 2H) 7.82 (dd,J=5.13, 0.73 Hz, 1H) 8.02 (s, 1H).

HRMS (ESI): calcd for C24H25N5O [M+H]+ 400.2132 found 400.2141.

N′-{4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyridin-2-yl}-N,N-dimethylethane-1,2-diamine

Yield 74%

HRMS (ESI): calcd for C26H30N5O [M+H]+ 443.2554 found 443.2555.

4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-(2-methoxyethyl)pyridin-2-amine

Yield 54%

¹H NMR (401 MHz, DMSO-d6) δ=3.15-3.21 (m, 2H) 3.24 (s, 3H) 3.37-3.42 (m,2H) 3.74 (s, 3H) 5.04 (br. s., 2H) 5.26 (s, 2H) 6.32 (dd, J=5.37, 1.22Hz, 1H) 6.34-6.41 (m, 2H) 6.47 (dt, J=7.60, 1.14 Hz, 1H) 6.50 (ddd,J=7.96, 2.23, 0.92 Hz, 1H) 6.70 (t, J=1.77 Hz, 1H) 6.90-6.99 (m, 3H)7.28-7.32 (m, 2H) 7.81 (d, J=5.25 Hz, 1H) 8.01 (s, 1H).

HRMS (ESI): calcd for C25H27N502[M+H]+ 430.2238 found 430.2242.

Method G Step e1-(3-{1-(4-methoxybenzyl)-4-[2-(methylamino)pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-3-[4-(trifluoromethyl)phenyl]urea

250 mg (0.65 mmol) of4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-methylpyridin-2-aminewere dissolved in 10 ml of dry dimethylformamide and 92 μl ofp-trifluoromethyl-phenylisocyanate were added. The reaction was stirredat room temperature overnight, poured into aqueous sodiumhydrogenocarbonate and extracted with dichloromethane. The organic phasewas then dried over sodium sulphate and evaporated. The residue waspurified by flash-chromatography on a silica gel column CH2C12-CH3COCH3;from 9/1 to 8/2), giving 234 mg (63%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) δ=2.69 (d, J=4.88 Hz, 3H) 3.74 (s, 3H) 5.30(s, 2H) 6.31 (s, 1H) 6.29-6.35 (m, 2H) 6.94 (d, J=8.79 Hz, 2H) 7.00 (dt,J=7.75, 1.25 Hz, 1H) 7.26 (m, J=8.79 Hz, 1H) 7.33 (d, J=8.79 Hz, 2H)7.47-7.55 (m, 2H) 7.58-7.69 (m, 4H) 7.87 (d, J=5.25 Hz, 1H) 8.10 (s, 1H)8.83 (s, 1H) 9.01 (s, 1H).

HRMS (ESI): calcd for C31H28F3N6O2 [M+H]+ 573.2221 found 573.2216.

Operating in an analogous way the following intermediates ureas wereobtained:

1-(3-{4-[2-(ethylamino)pyridin-4-yl]-1-(4-methoxybenzyl)-1H-pyrazol-3-yl}phenyl)-3-[4-(trifluoromethyl)phenyl]urea

Yield 58%

¹H NMR (401 MHz, DMSO-d6) δ=1.06 (t, J=7.14 Hz, 3H) 3.09-3.21 (m, 2H)3.74 (s, 3H) 5.30 (s, 2H) 6.28-6.35 (m, 3H) 6.91-6.96 (m, 2H) 6.97-7.03(m, 1H) 7.26 (t, J=7.87 Hz, 1H) 7.30-7.37 (m, 2H) 7.48-7.54 (m, 2H)7.58-7.68 (m, 4H) 7.82-7.87 (m, 1H) 8.08 (s, 1H) 8.83 (s, 1H) 9.02 (s,1H).

HRMS (ESI): calcd for C32H30F3N6O2 [M+H]+ 587.2377 found 587.2374.

1-{3-[4-(2-{[2-(dimethylamino)ethyl]amino}pyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)phenyl]urea

Yield 50%

¹H NMR (401 MHz, DMSO-d6) δ=2.16-2.23 (m, 6H) 2.41-2.53 (m, 2H)3.21-3.37 (m, 2H) 3.74 (s, 3H) 5.30 (s, 2H) 6.27 (bs, 1H) 6.35 (dd,J=5.31, 1.28 Hz, 1H) 6.37 (s, 1H) 6.91-6.96 (m, 2H) 6.96-7.01 (m, 1H)7.26 (t, J=7.87 Hz, 1H) 7.33 (d, J=8.67 Hz, 2H) 7.48-7.52 (m, 1H)7.52-7.54 (m, 2H) 7.58-7.67 (m, 4H) 7.86 (d, J=5.13 Hz, 1H) 8.88 (s, 1H)9.06 (s, 1H).

HRMS (ESI): calcd for C34H34F3N702[M+H]+ 630.2799 found 630.2822.

Method M Step a1-(3-{4-[2-(methylamino)pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-3-[4-(trifluoromethyl)phenyl]urea

200 mg (0.35 mmol) of1-(3-{1-(4-methoxybenzyl)-4-[2-(methylamino)pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-3-[4-(trifluoromethyl)phenyl]ureawere dissolved with 10 ml of trifluoroacetic acid and the solution wasstirred at 70° C. for 6 hours. The solvent was then evaporated and theresidue taken up with dichloromethane and washed with aqueous sodiumhydrogenocarbonate. The organic layer was dried over sodium sulphate andevaporated again, affording, after trituration with diethylether, 100 mg(63%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) (mixture of tautomers) δ=13.13 and 13.26 (2s,1H), 9.03 (m, 1H), 8.80 (m, 1H), 7.77 and 8.04 (2bs, 1H), 7.86 (d,J=5.37 Hz, 1H), 7.61-7.66 (m, 4H), 7.43-7.58 (3 m, 3H) 7.28 (m, 1H),6.21-6.42 (m, 3H), 2.68 (d, J=4.88 Hz, 3H).

HRMS (ESI): calcd for C23H20F3N5O [M+H]+ 453.1645 found 453.1638.

Operating in an analogous way the following compounds were obtained:

1-(3-{4-[2-(ethylamino)pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-3-[4-(trifluoromethyl)phenyl]urea

[(I)E, X═CH; R1, R3, R4, R5, R6=H; m=0; R2=ethylamino; Y═H;R7=4-trifluoromethylphenyl]

¹H NMR (401 MHz, DMSO-d6) δ=1.06 (t, J=7.08 Hz, 3H) 3.15 (dq, J=7.08,12.69 Hz, 2H) 6.30 (t, J=4.64 Hz, 1H) 6.33-6.38 (m, 2H), 7.03-7.08 (m,1H) 7.25-7.42 (m, 1H) 7.44-7.59 (2m, 2H) 7.56-7.69 (m, 4H), 7.83-7.88(m, 1H), 7.75 and 8.03 (2bs, 1H) 8.91 and 8.82 (2bs, 1H) 9.11 and 9.05(2 bs, 1H) 13.13 and 13.26 (2bs, 1H).

HRMS (ESI): calcd for C24H21F3N5O [M+H]+ 467.1802 found 467.1808.

1-{3-[4-(2-{[2-(dimethylamino)ethyl]amino}pyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)phenyl]urea

[(I)E, X═CH; R1, R3, R4, R5, R6=H; m=0; R2=(2-dimethylamino)ethylamino;Y═H; R7=4-trifluoromethylphenyl]

¹H NMR (401 MHz, DMSO-d6) (selected signals) (mixture of tautomers)δ=2.12 (s, 6H), 2.34 (t, J=6.71, 2H), 3.22 (q, J=6.23 Hz, 2H), 6.16 (t,J=5.37, 1H), 6.37 (dd, J=5.25, 1.22, 1H), 6.39-6.45 (br.s., 1H), 7.04(d, J=7.63 Hz, 1H), 7.59-7.67 (m, 4H), 7.86 (d, J=5.19 Hz, 1H), 13.25and 13.12 (2 br.s., 1H).

HRMS (ESI): calcd for C26H26F3N70 [M+H]+ 510.2224 found 510.2226.

Example 302,5-difluoro-N-(3-{4-[2-(methylamino)pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)benzenesulfonamide

[(I)C, X═CH; R1, R3, R4, R5, R6=H; m=0; R2=methylamino;R7′=2,5-difluorophenyl]

Method G Step c2,5-difluoro-N-(3-{1-(4-methoxybenzyl)-4-[2-(methylamino)pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)benzenesulfonamide

250 mg (0.65 mmol) of4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-methylpyridin-2-amine(prepared as described in Example 29) were dissolved in 10 ml of drypyridine and 87 μl of 2,5-difluorobenzensulfonylchloride were added Thereaction was stirred at room temperature overnight, then poured intoaqueous sodium hydrogenocarbonate and extracted with dichloromethane.The organic layer was dried over sodium sulphate and evaporated invacuo. The residue was then triturated with diethylether, giving 300 mgof the title compound (82%).

¹H NMR (401 MHz, DMSO-d6) δ=2.66 (d, J=4.88 Hz, 3H) 3.74 (s, 3H) 5.27(s, 2H) 6.19 (dd, J=5.25, 1.34 Hz, 1H) 6.21 (s, 1H) 6.30 (m, J=3.30 Hz,1H) 6.90-6.97 (m, 2H) 7.03-7.10 (m, 2H) 7.19-7.25 (m, 2H) 7.28-7.34 (m,2H) 7.44-7.60 (m, 3H) 7.81 (d, J=5.25, 1H) 8.07 (s, 1H) 10.78 (bs, 1H).

HRMS (ESI): calcd for C29H25F2N5O3S[M+H]+ 562.1719 found 562.1727.

Operating in an analogous way the following intermediate sulphonamidewas also obtained:

2,5-difluoro-N-{3-[1-(4-methoxybenzyl)-4-{2-[(2-methoxyethyl)amino]pyridin-4-yl}-1H-pyrazol-3-yl]phenyl}benzenesulfonamide

Yield 86%

¹H NMR (401 MHz, DMSO-d6) δ=3.23 (s, 3H) 3.27-3.42 (m, 4H), 3.74 (s, 3H)5.27 (s, 2H) 6.16 (dd, J=5.31, 1.40 Hz, 1H) 6.31 (s, 1H) 6.34-6.40 (m,1H) 6.91-6.95 (m, 2H) 7.02-7.10 (m, 2H) 7.19-7.24 (m, 1H) 7.23 (d,J=2.07 Hz, 1H) 7.29-7.33 (m, 2H) 7.45-7.58 (m, 3H) 7.79 (d, J=5.49 Hz,1H) 8.03 (s, 1H) 10.77 (s, 1H).

HRMS (ESI): calcd for C31H29F2N5O4S[M+H]+ 606.1981 found 606.1988.

Method M Step a2,5-difluoro-N-(3-{4-[2-(methylamino)pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)benzenesulfonamide

300 mg (0.53 mmol) of2,5-difluoro-N-(3-{1-(4-methoxybenzyl)-4-[2-(methylamino)-pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)benzenesulfonamidewere dissolved in 10 ml of trifluoroacetic acid and the mixture heatedat 70° C. under stirring for 4 hours. The solvent was then removed invacuo, the residue partitioned between dichloromethane and a saturatedaqueous solution of sodium hydrogenocarbonate. The organic layer wasdried over sodium sulphate and evaporated to dryness. The crude wasfinally purified by flash-chromatography on a silica gel column(CH2Cl₂-CH3COCH3; from 9/1 to 8/2), giving 47 mg (20%) of the titlecompound.

¹H NMR (401 MHz, DMSO-d6) (mixture of tautomers) δ=13.14 and 13.25 (2bs,1H), 10.78 (bs, 1H), 8.02 (s, 1H), 7.81 (m, 1H) 7.44-7.60 (m, 3H)7.05-7.39 (several m, 4H), 6.26-6.30 (m, 3H), 2.66 (d, J=4.88 Hz, 3H).

HRMS (ESI): calcd for C21H17F2N5O2S[M+H]+ 442.1144 found 442.1156.

Operating in an analogous way the following sulphonamide was alsoobtained:

2,5-difluoro-N-[3-(4-{2-[(2-methoxyethyl)amino]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]benzenesulfonamide

[(I)C, X═CH; R1, R3, R4, R5, R6=H; m=0; R2=(2-methoxy)ethylamino;R7′=2,5-difluorophenyl]

Yield 33%

¹H NMR (401 MHz, DMSO-d6) (selected signals) δ=13.14 and 13.25 (2s, 1H),10.78 (bs, 1H), 7.0-8.0 (several m, 8H), 3.33 (m, 2H), 3.31 (m, 2H),3.24 (s, 3H).

HRMS (ESI): calcd for C23H21F2N5O3S[M+H]+ 486.1406 found 486.1396.

Example 311-{3-[4-(2-aminopyrimidin-4-yl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)-phenyl]urea(Cpd. n^(o) 31)

[(I)E, X═N; R1, R3, R4, R5, R6=H; m=0; R2=NH2; Y═H;R7=4-trifluoromethylphenyl]

Method C Step i3-(3-nitrophenyl)-4-[(trimethylsilyl)ethynyl]-1H-pyrazole

415 mg (1.32 mmol) of 4-iodo-3-(3-nitrophenyl)-1H-pyrazole (prepared asdescribed in Example 27) were dissolved in 15 ml of dry tetrahydrofuranand 494 μL (3.42 mmol)of triethylamine, 80 mg (0.106 mmol) ofpalladium(II)-bis(triphenylphosphine) dichloride, 26 mg (0.166 mmol) ofcuprous iodide and 406 μL (2.9 mmol) of trimethylsilylacetylene wereadded consecutively in a nitrogen atmosphere. The reaction was refluxedunder stirring for 4 hours. The solvent was then removed in vacuo andthe residue re-dissolved with dichloromethane and washed with water. Theorganic phase was dried over sodium sulphate and evaporated, affording,after trituration with diisopropylether, 300 mg (80%) of the titlecompound, that was employed for the next step without any furtherpurification.

Step j

4-Ethynyl-3-(3-nitrophenyl)-1H-pyrazole

300 mg (1.05 mmol) of3-(3-nitrophenyl)-4-[(trimethylsilyl)ethynyl]-1H-pyrazole were suspendedin 60 ml of methanol and 120 mg (2.1 mmol) of potassium fluoride wereadded and the mixture stirred at room temperature overnight. After thistime the solvent was removed under reduced pressure and the residuetaken up with dichloromethane and washed with water. The organic layerwas then dried over sodium sulphate and evaporated. The crude wasfinally purified by flash-chromatography on a silica gel column(CH2C12-CH3COCH3 9/1), giving 150 mg (67%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) δ=4.37 (s, 1H) 7.78 (t, J=7.93 Hz, 1H) 8.24(d, J=8.30 Hz, 1H)) 8.26-8.29 (m, 1H) 8.47 (d, J=8.06 Hz, 1H) 8.91 (s,1H) 13.50 (bs, 1H). MS (ESI) (−) 212 m/z [M−H].

Step I 1-[3-(3-nitrophenyl)-1H-pyrazol-4-yl]ethanone

To a solution of 350 mg (1.6 mmol) of4-ethynyl-3-(3-nitrophenyl)-1H-pyrazole in a mixture of 50 ml of dioxaneand 0.5 ml (28 mmol) of water, 0.5 ml (6.5 mmol) of trifluoroacetic acidwere added. The reaction was heated at 100° C. under stirring for 2hours. The organic solvent was removed under reduced pressure and theresidue partitioned between ethylacetate and aqueous sodiumhydrogenocarbonate. The organic layer was then dried over sodiumsulphate and evaporated to dryness, affording, after trituration withdiethylether, 251 mg (68%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) δ=2.47 (s, 3H) 7.70 (t, J=7.93 Hz, 1H) 8.22(t, J=7.14 Hz, 2H) 8.64 (bs, 1H) 8.72 (s, 1H) 13.67 (bs, 1H).

HRMS (ESI): calcd for C11H9N303 [M+H]+ 232.0717 found 232.0719.

Protection of the Pyrazole:1-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]ethanone

320 mg (1.39 mmol) of 1-[3-(3-nitrophenyl)-1H-pyrazol-4-yl]ethanone weredissolved with 15 ml of dry dimethylformamide and 540 mg (1.66 mmol) ofcesium carbonate and 189 μl (1.39 mmol) of p-methoxybenzyl chloride wereadded. The reaction mixture was maintained at 70° C. under stirring for8 hours. The solvent was then removed under reduced pressure and theresidue taken up with dichloromethane and washed with water. The organiclayer was dried over sodium sulphate and evaporated. The crude wasfinally purified by flash-chromatography on a silica gel column(cyclohexane-ethylacetate; from 4/1 to 3/2), giving 470 mg (97%) of thetitle compound.

¹H NMR (401 MHz, DMSO-d6) δ=2.44 (s, 3H) 3.74 (br.s., 3H) 5.34-5.37 (m,2H) 6.91-6.97 (m, 2H) 7.31-7.37 (m, 2H) 7.69 (t, J=8.06 Hz, 1H)8.14-8.19 (m, 1H) 8.23 (ddd, J=8.21, 2.41, 1.10 Hz, 1H) 8.58-8.60 (m,1H) 8.80 (s, 1H).

HRMS (ESI): calcd for C19H17N304[M+H]+ 352.1292 found 352.1308.

Method C Step m(2E)-3-(dimethylamino)-1-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]prop-2-en-1-one

460 mg (1.3 mmol) of1-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-ethanone weredissolved in 25 ml of dry tetrahydrofuran and 15 ml of dimethylformamidedi-tert-butylacetale (62 mmol) were added to the resulting solution. Thereaction was heated at 70° C. under stirring for 6 hours. The solventwas then evaporated in vacuo and the residue diluted withdichloromethane and washed with water. The organic layer was finallydried over sodium sulphate and evaporated, giving 500 mg (96%) of thetitle compound as an oil.

¹H NMR (401 MHz, DMSO-d6) δ=2.65-3.12 (m, 6H) 3.73 (s, 3H) 5.32 (s, 2H)5.47 (d, J=12.33 Hz, 1H) 6.89-6.97 (m, 2H) 7.27-7.36 (m, 2H) 7.58 (d,J=12.45 Hz, 1H) 7.64 (t, J=8.06 Hz, 1H) 8.15-8.23 (m, 2H) 8.50 (s, 1H)8.67-8.71 (m, 1H). HRMS (ESI): calcd for C22H22N4O4 [M+H]+ 407.1714found 407.1724.

Step n4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyrimidin-2-amine

450 mg (1.1 mmol) of(2E)-3-(dimethylamino)-1-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]prop-2-en-1-onewere dissolved in 10 ml of dry dimethylformamide and 1.2 g (6.66 mmol)of guanidine carbonate and 910 mg (6.66 mmol) of potassium carbonatewere added. After 16 hours at 120° C. the solvent was removed in vacuoand the residue taken up with dichloromethane and washed with water. Theorganic phase was then dried over sodium to sulphate and evaporated. Thecrude was finally purified by flash-chromatography on a silica gelcolumn (CH2Cl₂-CH3COCH3 9/1), giving 300 mg (68%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) δ=3.74 (s, 3H) 5.36 (s, 2H) 6.42 (s, 2H) 6.52(d, J=5.13 Hz, 1H) 6.94 (d, J=8.79 Hz, 2H) 7.34 (d, J=8.79 Hz, 2H) 7.68(t, J=8.06 Hz, 1H) 8.07 (ddd, J=7.81, 1.59, 1.10 Hz, 1H) 8.13 (d, J=5.13Hz, 1H) 8.21 (ddd, J=8.24, 2.38, 0.98 Hz, 1H) 8.37 (s, 1H) 8.49 (t,J=1.89 Hz, 1H).

HRMS (ESI): calcd for C21H18N603 [M+H]+ 403.1513 found 403.1509.

Method G Step a4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]pyrimidin-2-amine

1.6 g (3.98 mmol) of4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-pyrimidin-2-aminewere dissolved in a mixture of 100 ml of dioxane and 30 ml of water and2.12 g (40 mmol) of ammonium chloride and 1.05 g (16 mmol) of metalliczinc were added successively. The reaction mixture was stirred at 100°C. for 6 hours. The suspension was then filtered through a celite padand the filtrate evaporated. The residue was partitioned betweendichloromethane and aqueous sodium hydrogenocarbonate, dried over sodiumsulphate and evaporated again, giving 1 g (67%) of the title compound.

HRMS (ESI): calcd for C21H20N5O [M+H]+ 373.1772 found 373.1771.

Step e1-{3-[4-(2-aminopyrimidin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)phenyl]urea

1 g (2.7 mmol) of4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-pyrimidin-2-aminewas dissolved in 290 ml of dry dimethylformamide and 386 μl ofp-trifluoromethyl-phenylisocyanate were added. The reaction was thenstirred at room temperature overnight. The mixture was poured intoaqueous sodium hydrogenocarbonate and extracted with dichloromethane.The organic layer was then dried over sodium sulphate and evaporated.The crude was purified by flash-chromatography on a silica gel column(CH2Cl₂-CH3COCH3; from 9/1 to 8/2), affording 800 mg (53%) of the titlecompound.

¹H NMR (401 MHz, DMSO-d6) δ=3.74 (s, 3H) 5.32 (s, 2H) 6.31 (d, J=5.25Hz, 1H) 6.42-6.47 (m, 2H) 6.93-6.96 (m, 2H) 7.10 (dt, J=7.69, 0.92 Hz,1H) 7.32-7.36 (m, 2H) 7.60-7.68 (m, 4H) 8.04 (d, J=5.25 Hz, 1H) 8.19 (s,1

H) 8.93 (s, 1H) 9.10 (s, 1H).

HRMS (ESI): calcd for C29H24F3N702 [M+H]+ 560.2017 found 560.2004.

Method M Step a1-{3-[4-(2-aminopyrimidin-4-yl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)-phenyl]urea

800 mg (1.4 mmol) of1-{3-[4-(2-aminopyrimidin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)phenyl]ureawere dissolved in 20 ml of trifluoroacetic acid and the mixture stirredat 70° C. for 4 hours. The solvent was then removed under reducedpressure and the residue taken up with dichloromethane and washed withaqueous sodium hydrogenocarbonate. The organic phase was dried oversodium sulphate and evaporated. The product was finally purified byflash-chromatography on a silica gel column (CH2Cl₂-CH3OH; from 99/1 to95/5), giving 450 mg (73%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) δ=6.39 (d, J=5.13 Hz, 1H) 6.45 (bs, 2H), 7.15(d, J=7.57 Hz, 1H) 7.27-7.70 (several m, 7H), 7.96 and 8.18 (2s, 1H,tautomers), 8.05 (d, J=5.25 Hz, 1H) 8.90 (2s, 1H, tautomers) 9.10 (2s,1H, tautomers), 13.23 and 13.33 (2s, 1H tautomers).

HRMS (ESI): calcd for C21H16F3N70 [M+H]+ 440.1441 found 440.1436.

Example 32N-(4-{3-[3-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-1H-pyrazol-4-yl}pyrimidin-2-yl)acetamide

(Cmpd. n^(o) 32) [(I)Z, R1, R3, R4, R5, R6=H; m=0; A=NHCONH;R7=4-trifluoromethylphenyl; R16=methyl]

Method L Step d

144 mg (0.33 mmol) of1-{3-[4-(2-aminopyrimidin-4-yl)-1H-pyrazol-3-yl]phenyl}-3-[4-(trifluoromethyl)phenyl]ureawere dissolved in 10 ml of dry tetrahydrofuran and 226 μl (1.32 mmol) ofN,N-diisopropyl-N-ethylamine and 94 μl of acetyl chloride were addedconsecutively. After 8 hours at room temperature the solvent was removedin vacuo and the residue taken up with dichloromethane and washed withan aqueous solution of sodium hydrogenocarbonate. The residue wasre-dissolved with 10 ml of methanol and stirred at room temperatureovernight. The solvent was then evaporated and the crude purified bypreparative HPLC(CH2Cl₂-ethanol 9/1), giving 79 mg (50%) of the titlecompound.

¹H NMR (401 MHz, DMSO-d6) δ=2.13 (s, 3H) 6.95 (m, 1H) 7.17 (m, 1H)7.60-7.67 (m, 7H) 8.21 (2s, 1H, tautomers) 8.44 (d, J=5.25 Hz, 1H) 8.91(2s, 1H, tautomers) 9.10 (2s, 1H, tautomers) 10.26 (s, 1H) 13.39-13.40(2s, 1H, tautomers).

HRMS (ESI): calcd for C23H18F3N702 [M+H]+ 482.1547 found 482.1540.

Example 33N-{3-[4-(2-aminopyrimidin-4-yl)-1H-pyrazol-3-yl]phenyl}-2,5-difluorobenzene-sulfonamide(Cmpd. n^(o) 34)

[(I)A, X═N; R3, R4, R5, R6=H; R2=NH2; A=—NHSO2-; R7=2,5-difluorophenyl]

Method G Step cN-{3-[4-(2-aminopyrimidin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl]phenyl}-2,5-difluorobenzenesulfonamide

175 mg (0.47 mmol) of4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-pyrimidin-2-aminewere dissolved with 10 ml of dry pyridine and 63 μl of2,5-difluorobenzensulfonylchloride were added under stirring. Thesolution was maintained at room temperature overnight. The reactionmixture was then poured into aqueous sodium hydrogenocarbonate andextracted with dichloromethane. The organic layer was dried over sodiumsulphate and evaporated to dryness. The residue was purified byflash-chromatography on a silica gel column (CH2Cl₂-CH3COCH3; from 9/1to 8/2), giving 80 mg (31%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) δ=3.74 (s, 3H) 5.29 (s, 2H) 6.12 (d, J=5.13Hz, 1H) 6.45 (s, 2H) 6.90-6.97 (m, 2H) 7.12-7.19 (m, 2H) 7.24-7.35 (m,4H) 7.47-7.60 (m, 3H) 7.97 (d, J=5.13 Hz, 1H) 8.16 (s, 1H) 10.79 (s,1H).

HRMS (ESI): calcd for C27H22F2N6O3S [M+H]+ 549.1515 found 549.1520.

Method M Step aN-{3-[4-(2-aminopyrimidin-4-yl)-1H-pyrazol-3-yl]phenyl}-2,5-difluorobenzene-sulfonamide

80 mg (0.14 mmol) ofN-{3-[4-(2-aminopyrimidin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazol-3-yl]phenyl}-2,5-difluorobenzenesulfonamidewere dissolved in 5 ml of trifluoroacetic acid and the resultingsolution was heated at 70° C. under stirring for 2 hours. The solventwas removed in vacuo and the residue taken up with dichloromethane andwashed with aqueous sodium hydrogenocarbonate. The organic phase wasthen dried over sodium sulphate and evaporated, giving, aftertrituration with diethylether, 10 mg (17%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) δ=6.19 (bs, 1H) 6.43 (bs, 2H) 7.10-8.18(several m, 9H), 10.79 and 10.92 (2s, 1H, tautomers), 13.24 and 13.30(2s, 1H, tautomers).

HRMS (ESI): calcd for C19H14F2N6O2S [M+H]+ 429.0940 found 429.0945.

Example 34N-(3-{4-[2-(ethylamino)pyrimidin-4-yl]-1H-pyrazol-3-yl}phenyl)-2,5-difluorobenzenesulfonamide(Cmpd. n^(o) 55)

(I)A, X═N; R3, R4, R5, R6=H; R2=ethylamino; A=—NHSO2—;R7=2,5-difluorophenyl]

Method C Step o1-(4-methoxybenzyl)-3-(3-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

1 g (2.3 mmol) of4-iodo-1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazole (prepared asdescribed in Example 27) was dissolved in 20 ml of dry toluene and 3.18ml of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (23 mmol), 20 mg (0.08mmol) of palladium(II) chloride diacetonitrile complex, 80 mg (0.005mmol) of S-Phos (2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)and 774 μl (5.7 mmol) of triethylamine were added successively. Thereaction mixture was submitted to microwave irradiation in a sealed vialat 90° C. for 30 minutes. The mixture was then filtered through a celitepad and the filtrate evaporated in vacuo. The residue was taken up withdichloromethane and washed with water and the organic layer dried oversodium sulphate and evaporated again. The crude was finally purified byflash-chromatography on a silica gel column (CH2Cl2-CH3COCH3 1%),affording 800 mg (80%) of the title compound, crystallized fromdiethylether.

¹H NMR (401 MHz, DMSO-d6) δ=1.28 (s, 12H) 3.73 (s, 3H) 5.33 (s, 2H)6.75-7.05 (m, 2H) 7.26-7.36 (m, 2H) 7.67 (t, J=7.99 Hz, 1H) 8.13 (s, 1H)8.17 (ddd, J=8.24, 2.38, 0.98 Hz, 1H) 8.25-8.37 (m, 1H) 8.91 (t, J=1.95Hz, 1H).

HRMS (ESI): calcd for C23H26BN3O5 [M+H]+ 435.2075 found 435.2066.

Step p4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-2-(methylsulfanyl)-pyrimidine

2.6 g (6 mmol) of1-(4-methoxybenzyl)-3-(3-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewere dissolved in a mixture of 520 ml of dioxane and 130 ml of waterunder a nitrogen atmosphere. 709 μl (6 mmol) of2-methylthio-4-chloro-pyrimidine, 3.9 g (12 mmol) of cesium carbonateand 650 mg (0.6 mmol) of palladium tetrakis were added consecutively tothe resulting solution under stirring. The reaction mixture was heatedat 100° C. for 6 hours, then filtered through a celite pad andconcentrated under reduced pressure. The residue was partitioned betweendichloromethane and water, the organic layer dried over sodium sulphateand evaporated to dryness. The crude was finally purified byflash-chromatography on a silica gel column (cyclohexane-ethylacetate;from 9/1 to 4/1), giving 2.3 g (88%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) δ=2.16 (s, 3H) 3.71 (s, 3H) 5.35 (s, 2H)6.87-6.96 (m, 2H) 7.18 (d, J=5.25 Hz, 1H) 7.28-7.39 (m, 2H) 7.66 (t,J=8.06 Hz, 1H) 7.94 (dt, J=7.99, 1.13 Hz, 1H) 8.21 (ddd, J=8.24, 2.38,1.10 Hz, 1H) 8.31 (t, J=1.83 Hz, 1H) 8.47 (d, J=5.25 Hz, 1H) 8.64 (s,1H).

HRMS (ESI): calcd for C22H19N5O3S [M+H]+ 434.1282 found 434.1278.

Method F Step a4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-2-(methylsulfonyl)-pyrimidine

2.3 g (5 mmol) of4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-2-(methylsulfanyl)pyrimidinewere dissolved with 50 ml of dry dichloromethane and 2.24 g (10 mmol) ofm-chloroperbenzoic acid 77% were added to the resulting solution. Thereaction was maintained at room temperature for 4 hours under stirring,then diluted with the same solvent and washed with a saturated aqueoussolution of sodium hydrogenocarbonate. The organic phase was dried oversodium sulphate and evaporated under reduced pressure. The residue wastriturated with diisopropylether and collected by filtration, giving 2.2g (95%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) δ=3.05 (s, 3H) 3.71 (s, 3H) 5.38 (s, 2H)6.86-7.03 (m, 2H) 7.24-7.44 (m, 2H) 7.66 (t, J=8.00 Hz, 1H) 7.78 (d,J=5.37 Hz, 1H) 7.89-8.06 (m, 1H) 8.23 (ddd, J=8.24, 2.38, 1.10 Hz, 1H)8.31 (t, J=1.95 Hz, 1H) 8.82 (s, 1H) 8.87 (d, J=5.37 Hz, 1H).

HRMS (ESI): calcd for C22H19N5O5S [M+H]+ 466.1180 found 466.1168.

Method F Step bN-ethyl-4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyrimidin-2-amine

450 mg (0.97 mmol) of4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-2-(methylsulfonyl)pyrimidinewere dissolved in a mixture of 10 ml of dioxane and 5 ml of ethylamine70% in water. The resulting solution was submitted to microwaveirradiation in a sealed vial at 140° C. for 45 minutes. The solvent wasthen removed and the residue was partitioned between dichloromethane andaqueous sodium hydrogenocarbonate. The organic phase was then dried oversodium sulphate and evaporated to dryness. 391 mg (94%) of the titlecompound were obtained by trituration with diethylether.

¹H NMR (401 MHz, DMSO-d6) δ=0.77-1.05 (m, 3H) 2.83-3.18 (m, 2H) 3.74 (s,3H) 5.35 (s, 2H) 6.60 (br. s., 1H) 6.86 (d, J=8.67 Hz, 1H) 6.91-6.98 (m,2H) 7.30-7.38 (m, 2H) 7.67 (t, J=8.06 Hz, 1H) 8.03 (d, J=7.69 Hz, 1H)8.16 (d, J=5.00 Hz, 1H) 8.21 (ddd, J=8.21, 2.41, 0.98 Hz, 1H) 8.39 (bs,1H) 8.46 (bs, 1H).

HRMS (ESI): calcd for C23H22N603 [M+H]+ 431.1826 found 431.1811.

Operating in an analogous way the following intermediate was obtained:

4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-N-(1-methylpiperidin-4-yl)pyrimidin-2-amine

(Microwave Irradiation was Performed at 130° C. for 1H. Yield: 81%)

¹H NMR (401 MHz, DMSO-d6) δ=1.19-1.95 (several m, 4H) 2.05-2.82 (severalm, 7H) 3.21-3.69 (m, 1H) 3.74 (s, 3H) 5.35 (s, 2H) 6.65 (br. s., 1H)6.86 (d, J=8.67 Hz, 1H) 6.91-6.97 (m, 2H) 7.31-7.39 (m, 2H) 7.68 (t,J=8.06 Hz, 1H) 7.99 (bs, 1H) 8.19 (d, J=5.13 Hz, 1H) 8.22 (ddd, J=8.18,2.26, 1.04 Hz, 1H) 8.33 (bs, 1H) 8.45 (bs, 1H).

HRMS (ESI): calcd for C27H29N703 [M+H]+ 500.2405 found 500.2387.

Method G Step a4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-ethylpyrimidin-2-amine

391 mg (0.91 mmol) ofN-ethyl-4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyrimidin-2-aminewere dissolved in a mixture of 20 ml of dioxane and 4 ml of water. 239mg (3.64 mmol) of metallic zinc and 485 mg (9.1 mmol) of ammoniumchloride were then added to the resulting solution. The reaction wascarried out at 100° C. under stirring for 5 hours. The suspension wasthen filtered through a celite pad and the filtrate evaporated in vacuo.The residue was partitioned between dichloromethane and aqueous sodiumhydrogenocarbonate and the organic layer dried over sodium sulphate andconcentrated to give a crude purified by flash-chromatography on asilica gel column (CH2Cl₂-CH3COCH3; from 9/1 to 7/3), affording 340 mg(93%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) δ=1.08 (t, J=7.14 Hz, 3H) 3.20-3.29 (m, 2H)3.74 (s, 3H) 5.08 (bs, 2H) 5.29 (s, 2H) 6.31 (d, J=5.13 Hz, 1H)6.51-6.58 (m, 2H) 6.70 (t, J=1.65 Hz, 1H) 6.87 (t, J=5.74 Hz, 1H)6.91-6.96 (m, 2H) 7.01 (t, J=7.81 Hz, 1H) 7.27-7.34 (m, 2H) 8.03 (d,J=5.13 Hz, 1H) 8.21 (bs, 1H).

HRMS (ESI): calcd for C23H24N5O [M+H]+ 401.2085 found 401.2093.

Operating in an analogous way the following intermediate was obtained:

4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-(1-methylpiperidin-4-yl)pyrimidin-2-amine

Yield: 82%

¹H NMR (401 MHz, DMSO-d6) δ=1.39-1.53 (m, 2H), 1.70-1.80 (m, 2H),1.88-2.06 (m, 2H), 2.18 (s, 3H), 2.68-2.76 (m, 2H), 3.55-3.59 (m, 1H),3.74 (s, 3H), 5.07 (bs, 2H), 5.29 (s, 2H), 6.34 (bs, 1H), 6.68-6.80 (m,4H), 6.93-6.96 (m, 2H), 7.00 (t, J=7.8 Hz, 1H), 7.30-7.34 (m, 2H), 8.04(d, J=5.0 Hz, 1H), 8.09-8.19 (bs, 1H).

HRMS (ESI): calcd for C27H31N70 [M+H]+ 470.2663 found 470.2668.

Step cN-(3-{4-[2-(ethylamino)pyrimidin-4-yl]-1-(4-methoxybenzyl)-1H-pyrazol-3-yl}phenyl)-2,5-difluorobenzenesulfonamide

340 mg (0.85 mmol) of4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-ethylpyrimidin-2-aminewere dissolved in 10 ml of dry pyridine and 114 μl (0.85 mmol) of2,5-difluorobenzensulfonyl chloride were added. The resulting solutionwas stirred at room temperature overnight. The mixture was then pouredinto aqueous sodium hydrogenocarbonate and extracted withdichloromethane. The organic layer was finally dried over sodiumsulphate and evaporated, giving 450 mg (91%) of the title compound.

¹H NMR (401 MHz, DMSO-d6) δ=0.98 (bs, 3H) 3.10 (bs, 2H) 3.75 (s, 3H)5.30 (s, 2H) 6.24 (bs, 1H) 6.86 (t, J=5.37 Hz, 1H) 6.94 (d, J=8.54 Hz,2H) 7.10-7.20 (m, 2H) 7.23-7.28 (m, 2H) 7.32 (d, J=8.67 Hz, 2H)7.45-7.61 (m, 3H) 8.02 (d, J=5.25 Hz, 1H) 8.27 (bs, 1H) 10.78 (s, 1H).

HRMS (ESI): calcd for C29H26F2N6O3S [M+H]+ 577.1828 found 577.1821.

Operating in an analogous way the following intermediate was obtained:

2,5-difluoro-N-{3-[1-(4-methoxybenzyl)-4-{3-[(1-methylpiperidin-4-yl)amino]phenyl}-1H-pyrazol-3-yl]phenyl}benzenesulfonamide

Yield: 89%

¹H NMR (401 MHz, DMSO-d6) δ=1.36-1.50 (m, 2H), 1.73-1.83 (m, 2H),1.90-2.08 (m, 2H), 2.16 (s, 3H), 2.65-2.73 (m, 2H), 3.55-3.59 (m, 1H),3.74 (s, 3H), 5.29 (s, 2H), 6.40 (bs, 1H), 6.79 (bs, 1H), 6.92-6.97 (m,2H), 7.13-7.19 (m, 2H), 7.26-7.34 (m, 4H), 7.47-7.60 (m, 3H), 8.04 (d,J=5.1 Hz, 1H), 8.16 (s, 1H), 10.79 (s, 1H).

HRMS (ESI): calcd for C33H33F2N7O3S [M+H]+ 646.2407 found 646.2419.

Method M Step aN-(3-{4-[2-(ethylamino)pyrimidin-4-yl]-1H-pyrazol-3-yl}phenyl)-2,5-difluorobenzenesulfonamide

450 mg (0.78 mmol) ofN-(3-{4-[2-(ethylamino)pyrimidin-4-yl]-1-(4-methoxybenzyl)-1H-pyrazol-3-yl}phenyl)-2,5-difluorobenzenesulfonamidewere dissolved in 10 ml of trifluoroacetic acid and the resultingsolution heated at 70° C. under stirring for 4 hours. After this timethe solvent was evaporated and the residue taken up with dichloromethaneand washed with aqueous sodium hydrogenocarbonate. The organic phase wasthen dried over sodium sulphate and evaporated again. The crude wasfinally purified by flash-chromatography on a silica gel column(CH2Cl₂-CH3COCH3; from 9/1 to 8/2), giving 80 mg (22%) of the titlecompound.

¹H NMR (401 MHz, DMSO-d6) δ=1.02 (t, J=7.02 Hz, 3H). 3.15 (q, J=5.80 Hz,2H) 6.35 (d, J=5.19 Hz, 1H) 6.49 (bs, 1H) 7.08-7.39 (m, 5H),), 7.39-7.54(2m, 2H) 8.02 (m, 1H), 8.10 (m, 1H) 10.53 (bs, 1H) 13.04 (bs, 1H).

HRMS (ESI): calcd for C21H18F2N6O2S [M+H]+ 457.1253 found 457.1250.

Operating in an analogous way the following compound was obtained:

2,5-difluoro-N-[3-(4-{2-[(1-methylpiperidin-4-yl)amino]pyrimidin-4-yl}-1H-pyrazol-3-yl)phenyl]benzenesulfonamide

[(I)A, X═N; R3, R4, R5, R6=H; R2=(1-methylpiperidin-4-yl)amino;A=—NHSO2—; R7=2,5-difluorophenyl]

Yield: 26%

¹H NMR (401 MHz, DMSO-d6) δ=2.25 (s, 3H) 2.50 (m, 4H) 2.73 (m, 4H) 3.38(m, 1H) 6.40 (bs, 1H), 6.79 (d, J=7.32

Hz, 1H) 7.05-7.29 (m, 4H) 7.38-7.64 (m, 3H) 8.04 (m, 2H) 10.47 (bs, 1H)13.22 (bs, 1H).

HRMS (ESI): calcd for C21H18F2N6O2S [M+H]+ 526.1831 found 526.1834.

Example 35N-[3-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide(Cmpd. n^(o) 52)

[(I)C, X═CH; R1=Me, R2, R4, R5=H; R3, R6=F; m=0; R7′=2,5-difluorophenyl]

Preparation of 2-bromo-1,3-difluoro-4-nitrobenzene [(35), G=NO2; L′=Br;R3, R6=F; R4, R5=H]

To a stirred, ice-cooled, solution of 1,3-difluoro-2-bromobenzene (1.74g, 9.0 mmol) in 96% sulphuric acid (2 mL), a mixture of 96% sulphuricacid (0.6 mL) and fuming nitric acid (0.6 mL) was slowly added, keepingthe temperature below 55° C. After addition, the reaction mixture wasstirred at room temperature for 2 h, then poured onto ice. Theprecipitate was filtered, washed with water and dried. The titlecompound was obtained as a yellowish solid (1.7 g, 80%).

HPLC (254 nm): R_(t): 6.26 min.

¹H-NMR (401 MHz, DMSO-d6) δ=8.1 (m, 1H) 7.1 (m, 1H).

Preparation of1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[(21), PG3=tetrahydro-2H-pyran-2-yl;M=4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]

To a cooled (−78° C.), stirred solution of1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (prepared as described in theliterature: J. Med. Chem. 2004, 47, 2995-3008 and JOC 2008, 73,4309-4312) (11.8 g, 78 mmol) in anhydrous THF (200 mL), 2.5 M n-BuLi inn-hexane (40 mL, 100 mmol) was slowly added, keeping T<−70° C. Afteraddition the mixture was stirred at −78° C. for 1 h, then triisopropylborate (23 mL, 100 mmol) was added dropwise, keeping T<−70° C. Afteraddition the mixture was let to reach room temperature in about 2 h,then a solution of 2,3-dimethyl-2,3-butandiol (12.5 g, 105 mmol) inanhydrous THF (30 mL) was added, followed after 10 min by glacial aceticacid (6 mL, 100 mmol). The colorless jelly precipitate was filtered on athick celite pad and washed thoroughly with diethyl ether. The filtratewas concentrated to yield a colorless oil that crystallized uponaddition of n-heptane. The title compound was obtained as colorlesscrystalline powder (14.7 g, 53%).

HPLC (254 nm): R_(t): 5.81 min.

¹H-NMR (401 MHz, DMSO-d6) δ=7.55 (s, 1H) 6.7 (s, 1H) 5.75 (m, 1H) 4.05(m, 1H) 3.7 (m, 1H) 2.5 (m, 1H) 1.85-2.2 (m, 2H) 1.4-1.75 (m, 3H) 1.2(s, 12H).

ESI (+) MS: m/z 279 (MH+).

Method C Step q5-(2,6-Difluoro-3-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

To a solution of tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.04mmol) in dimethoxyethane (30 mL), 2-bromo-1,3-difluoro-4-nitrobenzene(2.38 g, 10 mmol) in dimethoxyethane (20 mL) was added and the mixturewas insufflated with nitrogen for 10 min. To the solution,1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(4 g, 15 mmol) in dimethoxyethane (30 mL) was added and the mixture wasinsufflated with nitrogen for 2 min, then 2 M sodium carbonate solution(40 mL) was added and the mixture was refluxed for 4 h. The mixture wascooled and the organic phase was concentrated to oil. By addition ofdiethyl ether a precipitate was obtained, filtered off and discarded.The filtrate was concentrated and purified by flash chromatography(eluant: dichloromethane/ethyl acetate 20:1). The title compound wasobtained as oil (1.27 g, 40%).

HPLC (254 nm): R_(t): 4.38 min.

¹H-NMR (401 MHz, DMSO-d6) δ=8.4 (m, 1H) 7.7 (s, 1H) 7.5 (m, 1H) 6.6 (s,1H) 5.2 (m, 1H) 3.7 (m, 1H) 3.3 (m, 1H) 2.2 (m, 1H) 1.9 (m, 2H) 1.6 (m,1H) 1.4 (m, 2H). ESI (+) MS: m/z 310 (MH+).

Step r4-bromo-5-(2,6-difluoro-3-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

A solution of5-(2,6-difluoro-3-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(1.23 g, 4 mmol) and N-bromosuccinimide (1.25 g, 7 mmol) indichloromethane (10 mL) was stirred at room temperature for 18 h. Thesolution was washed with water, dried over anhydrous sodium sulfate andconcentrated. Crude4-bromo-5-(2,6-difluoro-3-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolewas obtained.

HPLC (254 nm): R_(t): 7.08 min.

¹H-NMR (401 MHz, DMSO-d6) δ=8.5 (m, 1H) 7.9 (s, 1H) 7.6 (m, 1H) 5.25 (m,1H) 3.7 (m, 1H) 3.4 (m, 1H) 2.2 (m, 1H) 1.9 (m, 2H) 1.6 (m, 1H) 1.4 (m,2H).

ESI (+) MS: m/z 390 (MH+).

Step s 4-Bromo-5-(2,6-difluoro-3-nitrophenyl)-1H-pyrazole

The crude product was dissolved in 1.25 M hydrochloric acid in methanol(10 mL) and stirred at room temperature for 3 h. A saturated aqueoussolution of sodium hydrogencarbonate was added and the product wasextracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate and concentrated to oil. After addition of a1:1 mixture of diisopropyl ether and petroleum ether the desiredcompound crystallized as an off-white solid (0.67 g, 55% two steps).

HPLC (254 nm): R_(t): 3.97 min.

¹H NMR (401 MHz, DMSO-d6, hydrochloride) δ=7.51-7.59 (m, 1H) 8.19 (bs,1H) 8.35-8.48 (m, 1H) 13.78 (bs, 1

H).

ESI (+) MS: m/z 303 (MH−).

Step d 4-Bromo-3-(2,6-difluoro-3-nitrophenyl)-1-methyl-1H-pyrazole

To a mixture of 4-bromo-5-(2,6-difluoro-3-nitrophenyl)-1H-pyrazole (0.88g, 2.9 mmol) and methyl iodide (2 mL, 32 mmol) in dichloromethane (20mL), tetrabutylammonium bromide (0.32 g, 1 mmol) in 7 N sodium hydroxide(20 mL) was added and the mixture was rapidly stirred at roomtemperature for 3 h. The phases were separated and the organic layer waswashed with water, dried over anhydrous sodium sulfate and concentrated.The crude residue was purified by flash chromatography (eluant:dichloromethane/petroleum ether 2:1). The title compound, mixture of thetwo regioisomers, was obtained as a waxy solid (0.53 g, 57%).

HPLC (254 nm): R_(t): 4.42 min.

ESI (+) MS: m/z 319 (MH+).

Preparation ofN-[3-(4-bromo-1-methyl-1H-pyrazol-3-yl)-2,4-difluorophenyl]-2,5-difluorobenzenesulfonamide

A mixture of 4-bromo-3-(2,6-difluoro-3-nitrophenyl)-1-methyl-1H-pyrazoleand its regioisomer4-bromo-5-(2,6-difluoro-3-nitrophenyl)-1-methyl-1H-pyrazole (0.35 g, 1.1mmol), powdered zinc (0.39 g, 6 mmol) and ammonium chloride (0.6 g, 11mmol) in dioxane (6 mL) and water (2 mL) were refluxed under goodstirring for 3 h. After cooling, the mixture was filtered and thefiltrate was concentrated. The residue was taken up withdichloromethane, washed with saturated aqueous solution of sodiumhydrogen carbonate and water, dried over anhydrous sodium sulfate andconcentrated. The crude mixture of3-(4-bromo-1-methyl-1H-pyrazol-3-yl)-2,4-difluoroaniline and itsregioisomer 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2,4-difluoroaniline wasobtained as a brownish solid (0.33 g, 95%).

HPLC (254 nm): R_(t): 3.49 min and 3.81 min.

ESI (+) MS: m/z 290 (MH+).

To an ice-cooled solution of a mixture of3-(4-bromo-1-methyl-1H-pyrazol-3-yl)-2,4-difluoroaniline and itsregioisomer 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2,4-difluoroaniline inanhydrous pyridine (3 mL), 2,5-difluorosulfonyl chloride (0.23 g, 1.1mmol) was added and the reaction mixture was stirred at room temperaturefor 18 h. More sulfonyl chloride (0.14 g, 0.7 mmol) was added and, after2 h stirring, dichloromethane was added and the solution was washedtwice with 2 N hydrochloric acid, with saturated aqueous solution ofsodium hydrogen carbonate, dried over anhydrous sodium sulfate andconcentrated. The residue was crystallized from diethyl ether and thetitle compound was obtained as a yellow solid (0.35 g, 68%).

HPLC (254 nm): R_(t): 4.59 min.

¹H NMR (401 MHz, DMSO-d6) δ=3.88 (s, 3H) 7.16 (t, J=8.61 Hz, 1H) 7.40(td, J=8.94, 5.92 Hz, 1H) 7.44-7.61 (m, 2H) 8.07 (s, 1H) 10.68 (bs, 1H).

ESI (+) MS: m/z 466 (MH+).

Step hN-[3-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide

To a solution of tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.1mmol) in dimethoxyethane (3 mL),N-[3-(4-bromo-1-methyl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluorobenzenesulfonamide(0.14 g, 0.3 mmol) in dimethoxyethane (3 mL) was added and the mixturewas insufflated with nitrogen for 5 min. A solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.63mmol) in dimethoxyethane (3 mL) was added and the mixture wasinsufflated with nitrogen for 10 min, then 2 M sodium carbonate solution(2.5 mL) was added and the mixture was heated at 110° C. in a microwavecavity for 3 h. The mixture was cooled and the organic phase wasconcentrated. The crude oil was purified by flash chromatography(eluant: dichloromethane/ethyl acetate 1:1). The title compound wasobtained as a white solid (0.05 g, 36%).

HPLC (254 nm): R_(t): 5.33 min.

¹H-NMR (401 MHz, DMSO-d6) δ=10.68 (bs, NH) 8.22-8.51 (m, 3H), 7.51-7.59(m, 1H) 7.37-7.49 (m, 3H), 7.20 (td, J=8.85, 1.46 Hz, 1H), 6.92-7.01 (m,2H), 3.93 (s, 3H).

HRMS (ESI) calcd for C21H14F4N4O2S [M+H]+ 463.0847, found 463.0851.

Example 36N-[3-(1-i-Butyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide(Cm pd. n^(o) 56) [(I)C, X═CH; R1=isobutyl; R2, R4, R5=H; R3, R6=F; m=0;R7′=2,5-difluorophenyl]

Method C Steps s and dN-{3[4-bromo-1-(2-methylpropyl)-1H-pyrazol-3-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide

4-Bromo-5-(2,6-difluoro-3-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(prepared as described in Example 35) (0.53 g, 1.38 mmol), powdered zinc(0.52 g, 8 mmol) and ammonium chloride (0.8 g, 15 mmol) in dioxane (10mL) and water (5 mL) were refluxed under vigorous stirring for 1.5 h.After cooling, the mixture was filtered and the filtrate wasconcentrated. The residue was taken up with dichloromethane, washed withsaturated aqueous solution of sodium hydrogen carbonate and water, driedover anhydrous sodium sulfate and concentrated. To the crude3-[4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-2,4-difluoroaniline,dissolved in toluene (10 mL) and anhydrous pyridine (2 mL),2,5-difluorobenzenesulfonyl chloride (0.64 g, 3 mmol) was added and thereaction mixture was stirred at room temperature for 18 h.Dichloromethane and water were added and the organic layer was washedtwice with 0.5 N hydrochloric acid, with saturated aqueous solution ofsodium hydrogen carbonate, dried over anhydrous sodium sulfate andconcentrated. CrudeN-{3[4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-2,4-difluorophenyl}-N-[(2,5-difluoro-phenyl)sulfonyl]-2,5-difluorobenzenesulfonamide was isolated as a yellow oily foam in quantitative yield.

HPLC (254 nm): R_(t): 6.07 min.

ESI (+) MS: m/z 712 (MH+).

The raw product was dissolved in 1.25 M hydrochloric acid in methanol (8mL) and stirred at room temperature for 18 h. After solvent removalcrudeN-[3-(4-bromo-1H-pyrazol-3-yl)-2,4-difluorophenyl]-N-[(2,5-difluorophenyl)sulfonyl]-2,5-difluoro-benzenesulfonamidewas obtained (quant.).

HPLC (254 nm): R_(t): 5.24 min.

ESI (+) MS: m/z 628 (MH+).

To the residue, dissolved in dichloromethane (10 mL), isobutyl bromide(1 mL, 9 mmol) and tetrabutylammonium bromide (0.16 g, 0.5 mmol) in 7 Nsodium hydroxide (10 mL) were added and the mixture was vigorouslystirred at room temperature. After 2 h, onlyN-[3-(4-bromo-1H-pyrazol-3-yl)-2,4-difluorophenyl]-2,5-difluorobenzene-sulfonamidewas present. Upon addition of more isobutyl bromide (3 mL, 27 mmol) andtetrabutylammonium bromide (0.45 g, 1.4 mmol) and after 18 h additionalstirring the reaction was completed. The phases were separated and theorganic layer was washed with water, dried over anhydrous sodium sulfateand concentrated. The crude residue was purified by flash chromatography(eluant: dichloromethane). First the regioisomerN-{3-[4-bromo-1-(2-methylpropyl)-1H-pyrazol-5-yl]-2,4-difluorophenyl}-2,5-difluoro-benzenesulfonamide(0.065 g, 0.13 mmol) was isolated, then the title product was obtainedas a white solid (0.12 g, 0.2 mmol, 15% four steps).

HPLC (254 nm): R_(t): 5.29 min.

¹H-NMR (401 MHz, DMSO-d6) δ=10.67 (s, NH) 8.12 (s, 1H), 7.57-7.64 (m,1H) 7.51-7.57 (m, 1H) 7.47 (td, J=5.19, 2.69 Hz, 1H) 7.38-7.45 (m, 1H),7.21 (td, J=8.94, 1.40 Hz, 1H), 3.95 (d, J=7.20 Hz, 2H), 2.09 (m, 1H),0.83 (d, J=6.59 Hz, 6H).

HRMS (ESI) calcd for C19H16BrF4N3O2S [M+H]+ 506.0156, found 506.0161.

Step hN-[3-(1-i-butyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide

To a solution of tetrakis(triphenylphosphine)palladium(0) (0.035 g, 0.03mmol) in dimethoxyethane (1 mL),N-{3-[4-bromo-1-(2-methylpropyl)-1H-pyrazol-3-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide(0.09 g, 0.18 mmol) in dimethoxyethane (1 mL) was added and the mixturewas insufflated with nitrogen for 5 min. A solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.08 g, 0.4mmol)) in dimethoxyethane (1 mL) was added and the mixture wasinsufflated with nitrogen for 10 min, then 2 M sodium carbonate solution(1 mL) was added and the mixture was heated at 110° C. in a microwavecavity for 1 h. More tetrakis(triphenylphosphine)palladium(0) (0.012 g,0.01 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(0.016 g, 0.08 mmol) were added and the process was resumed for 0.5 h.The mixture was cooled and the organic phase was concentrated. The crudeoil was purified by flash chromatography (eluant:dichloromethane/methanol 30:1). The title compound was obtained as awhite solid (0.025 g, 28%).

HPLC (254 nm): R_(t): 4.62 min.

¹H-NMR (401 MHz, DMSO-d6) δ=10.66 (bs, NH) 8.43 (s, 1H), 8.35-8.41 (m,2H), 7.51-7.59 (m, 1H) 7.39-7.50 (m, 3H) 7.14-7.27 (m, 1H), 6.96-7.03(m, 2H) 4.00 (d, J=7.20 Hz, 2H), 2.15 (m, 1H), 0.88 (d, J=6.71 Hz, 6H).

HRMS (ESI) calcd for C24H20F4N4O2S [M+H]+ 505.1316, found 505.1305.

Example 37(2,5-Difluoro-benzyl)-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amine[(I), X═CH; R1, R2, R4, R5=H; R3, R6=F; m=0; A=—NHCH2—;R7=2,5-difluorophenyl]

Dibenzyl-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amine(prepared as described in Example 22) (150 mg, 0.551 mmol) was dissolvedin a 1:1:1 mixture of methanol, acetic acid and water (18 mL). Freshlydistilled 2,5-difluorobenzaldehyde (0.180 mL, 1.653 mmol, 3 eq) was thenadded, followed by sodiumcyanoborohydride (2.424 mmol, 4.4 eq) and themixture was stirred at room temperature for 5 hours. It was then pouredinto water, basified to pH 10 by addition of a saturated aqueoussolution of Na₂CO₃ and extracted with ethyl acetate (3×30 mL). Thecombine dorganic layers were washed with brine, dried over Na₂SO₄ andevaporated to dryness. The crude product was purified by flashchromatography on silica gel (DCM/MeOH 96:4) to give 124 mg (85%) of(2,5-difluoro-benzyl)-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-aminea white solid.

HPLC (254 nm): R_(t): 5.75 min.

¹H-NMR (401 MHz, DMSO-d6) δ=13.51 (s, 1H), 8.46-8.49 and 8.13-8.15 (2 m,1H, 2 tautomers), 8.38-8.44 (m, 2H), 7.19-7.30 (m, 2H), 7.10-7.19 (m,3H), 6.91-7.07 (m, 1H), 6.65-6.81 (m, 1H), 6.11 and 6.28 (2t, 1H, 2tautomers), 4.37-4.43 (m, 1H).

HRMS (ESI) calcd for C21H15F4N4 [M+H]+ 399.1228, found 399.1236.

Preparation ofN-(3-Acetyl-2,4-difluoro-phenyl)-2,5-difluoro-N-(2-methoxyethoxymethyl)-benzenesulfonamide

[(1), R4, R5=H; R3, R6=F;G=N-(methoxyethoxymethyl)-(2,5-difluorobenzenesulfonylamino)]

N-(3-acetyl-2,4-difluoro-phenyl)-2,5-difluoro-benzenesulfonamide

1-(2,6-Difluoro-3-nitro-phenyl)-ethanone (J. Het. Chem. 1987, 24, 1509)(3.8 g, 18.9 mmol) was dissolved in ethyl acetate (40 mL). Pd/C5% (1.2g) was added and the mixture was shaken under hydrogen atmosphere (2atm) in a Parr apparatus for 8 hours. The reaction mixture was thenfiltered on a Celite pad and the filtrate was evaporated to dryness. Thecrude 1-(3-amino-2,6-difluoro-phenyl)-ethanone was immediately dissolvedin dry pyridine (80 mL) under nitrogen atmosphere, neat2,5-difluorobenzenesulfonylchloride was then added dropwise (2.55 mL,18.9 mmol, 1 eq) and the mixture was stirred at room temperatureovernight. The solvent was then concentrated under reduced pressure andthe residue was taken up with DCM (100 mL) and washed withhalf-saturated aqueous ammonium chloride and brine. The organic phasewas dried over Na₂SO₄ and evaporated to dryness. The crude was treatedwith a 1:1 diethyl ether/n-hexane mixture and stirred until a solid wasobtained. The solid was filtered and dried under vacuum at 45° C. for 2hours to give 5.4 g ofN-(3-acetyl-2,4-difluoro-phenyl)-2,5-difluoro-benzenesulfonamide as alight orange powder (82% over two steps).

HPLC (254 nm): R_(t): 5.79 min.

¹H-NMR (401 MHz, DMSO-d6) δ=10.75 (br. s., 1H), 7.39-7.72 (m, 4H), 7.20(td, J=1.6, 9.2 Hz, 1H), 2.48 (t, J=1.6 Hz, 3H).

N-(3-Acetyl-2,4-difluoro-phenyl)-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzenesulfonamide

N-(3-acetyl-2,4-difluoro-phenyl)-2,5-difluoro-benzenesulfonamide (2.88g, 8.293 mmol) was dissolved in dry DCM (75 mL) under nitrogenatmosphere. DIPEA (1.55 mL, 9.12 mmol, 1.1 eq) was then added, followedby 2-methoxyethoxymethyl chloride (0.98 mL, 9.12 mmol, 1.1 eq) and themixture was stirred at room temperature for 1 h. It was then dilutedwith DCM and washed with water and brine, dried over Na₂SO₄ andevaporated to dryness. The crude product was purified by chromatographyon silica gel (n-hexane/ethyl acetate 7:3) to give 2.25 g (62%) ofN-(3-acetyl-2,4-difluoro-phenyl)-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzene-sulfonamideas a yellow oil.

HPLC (254 nm): R_(t): 6.38 min.

¹H-NMR (401 MHz, DMSO-d6) δ=7.65-7.73 (m, 1H), 7.57-7.65 (m, 1H),7.47-7.57 (m, 2H), 7.29 (td, J=1.5, 9.2 Hz, 1H), 5.11 (s, 2H), 3.65-3.70(m, 2H), 3.40-3.45 (m, 2H), 3.29 (s, 3H), 3.21 (s, 3H).

HRMS (ESI) calcd for C18H18F4NO5F [M+H]+: 453.1120, found: 453.1104.

Example 38N-{3-[4-(2-Amino-pyridin-4-yl)-1-ethyl-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide

(Cpd. n^(o) 68) [(I)U, R1, R4, R5=H; R3, R6=F; m=2; A=—NHSO2—;R7=2,5-difluorophenyl]

Method C Steps a and bN-[2,4-Difluoro-3-(1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-N-(2-methoxyethoxy-methyl)-benzenesulfonamide

[(23), R4, R5=H; R3, R6=F;G=N-(methoxy-ethoxymethyl)-(2,5-difluorobenzenesulfonylamino)]

N-(3-acetyl-2,4-difluoro-phenyl)-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzene-sulfonamide(1.7 g, 3.91 mmol) was dissolved in dry toluene (40 mL) under nitrogenatmosphere. N,N-dimethylformamidedimethylacetal (2.1 mL, 15.64 mmol, 4eq) was added and the mixture was heated to 100° C. and stirred at thistemperature for 4 hours. The solvent was then evaporated to dryness. Thecrude intermediate enaminone was kept under high vacuum for 2 hours andthen dissolved in absolute ethanol (26 mL). Monohydrate hydrazine wasadded (0.57 mL, 11.7 mmol, 3 eq) and the reaction mixture was heated to60° C. and stirred at this temperature for 2 hours. It was thenconcentrated under reduced pressure, taken up with DCM and washed withwater and brine. The crude product was purified by chromatography onsilica gel (DCM/MeOH 95:5) to give 1.27 g ofN-[2,4-difluoro-3-(1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-N-(2-methoxyethoxy-methyl)-benzenesulfonamideas a yellow amorphous solid.

HPLC (254 nm): R_(t): 5.89 min.

¹H-NMR (401 MHz, DMSO-d6) δ=13.22 (br. s., 1H), 7.87 (br. s., 1H),7.51-7.74 (m, 3H), 7.30-7.39 (m, J=6.8 Hz, 1H), 7.15-7.27 (m, 1H), 6.43(br. s., 1H), 5.13 (s, 2H), 3.64-3.80 (m, 2H), 3.40-3.49 (m, 2H), 3.22(s, 3H).

HRMS (ESI) calcd for C19H18F4N3O4F [M+H]+: 460.0949, found: 460.0949.

Method C Step cN-[3-(4-Bromo-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzene-sulfonamide[(25), R4, R5=H; R3, R6=F; Hal=Br;G=N-(methoxyethoxymethyl)-(2,5-difluorobenzene-sulfonylamino)]

N-[2,4-difluoro-3-(1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-N-(2-methoxyethoxy-methyl)-benzenesulfonamide(1.27 g, 2.76 mmol) was dissolved in dry DCM (10 mL). N-bromosuccinimidewas then added (737 mg, 4.14 mmol, 1.5.eq) and the reaction was stirredat room temperature for 3 hours. The reaction mixture was then dilutedwith DCM and washed with 10% aqueous NaHSO₃ and brine. The organic phasewas dried over Na₂SO₄ and evaporated to dryness. The desiredN-[3-(4-bromo-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-N-(2-methoxyethoxymethyl)-benzenesulfonamidewas isolated from the crude mixture by chromatography on silica gel(DCM/MeOH 95:5) obtaining 584 mg (39%) of off-white solid.

¹H-NMR (300 MHz, DMSO-d6) δ=13.61 (br. s., 1H), 8.14 (br. s., 1H),7.46-7.73 (m, 4H), 7.25-7.39 (m, 1H), 5.13 (s, 2H), 3.68-3.75 (m, 2H),3.40-3.49 (m, 2H), 3.22 (s, 3H).

Step dN-[3-(4-Bromo-1-ethyl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzenesulfonamide[(26), R1, R4, R5=H; R3, R6=F; m=2; Hal=Br;G=N-(methoxyethoxymethyl)-(2,5-difluorobenzenesulfonylamino)]

N-[3-(4-bromo-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzenesulfonamide(584 mg, 1.085 mmol) was dissolved in DCM (5 mL). 32% sodium hydroxidewas added (5 mL) followed by ethyl iodide (0.13 mL, 1.628 mmol, 1.5 eq)and TBAB (58 mg, 0.18 mmol, 0.17 eq) and the biphasic mixture wasvigorously stirred at room temperature for 3 hours. The reaction mixturewas then diluted with DCM, washed with water and brine, dried overNa₂SO₄ and evaporated to dryness. The two ethyl pyrazole regioisomershave been separated by chromatography on silica gel (n-hexane/ethylacetate 7:3): 308 mg (50% yield) of the desired regioisomerN-[3-(4-bromo-1-ethyl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzenesulfonamidewere obtained along with 160 mg (26% yield) of the minor regioisomerN-[3-(4-bromo-2-ethyl-2H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzenesulfonamide.

HPLC (254 nm): R_(t): 6.92 min.

¹H-NMR (401 MHz, DMSO-d6) δ=8.15 (s, 1H), 7.63-7.70 (m, 1H), 7.55-7.63(m, 1H), 7.47-7.55 (m, 2H), 7.30 (td, J=1.4, 8.9 Hz, 1H), 5.13 (s, 2H),4.18 (q, J=7.3 Hz, 2H), 3.67-3.73 (m, 2H), 3.41-3.47 (m, 2H), 3.22 (s,3H), 1.38 (t, J=7.3 Hz, 3H).

HRMS (ESI) calcd for C21H21BrF4N3O4S [M+H]+: 566.0367, found: 566.0354.

Step hN-[3-(1-Ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzenesulfonamide[(II), X═CH; R1, R2, R4, R5=H; R3, R6=F; m=2;G=N-(methoxyethoxymethyl)-2,5-difluorobenzene-sulfonylamino]

In a vial suitable for microwave irradiationN-[3-(4-Bromo-1-ethyl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzenesulfonamide(288 mg, 0.509 mmol) was dissolved in dimethoxyethane (4.5 mL) and Arwas bubbled through the solution for 5 minutes. Water (0.5 mL) wasadded, followed by 4-pyridylboronic acid pinacol ester (209 mg, 1.018mmol, 2 eq), cesium carbonate (497 mg, 1.527 mmol, 3 eq) andPd(dppf)Cl₁₂.DCM (42 mg, 0.051 mmol, 0.1 eq). The vial was sealed andirradiated in the microwave oven at 100° C. for 30 minutes. The reactionmixture was then filtered over a Celite pad and concentrated underreduced pressure. The residue was taken up with ethyl acetate and washedwith saturated aqueous NaHCO₃ and brine. The organic phase was driedover Na₂SO₄ and evaporated to dryness. The crude product was purified bychromatography on silica gel (DCM/MeOH 97:3) to give 247 mg (86% yield)ofN-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzenesulfonamideas an off-white solid.

HPLC (254 nm): R_(t): 6.14 min.

¹H-NMR (401 MHz, DMSO-d6) δ=8.47 (s, 1H), 8.39-8.42 (m, 2H), 7.57-7.65(m, 1H), 7.45-7.55 (m, 3H), 7.24-7.31 (m, 1H), 7.01-7.07 (m, 2H), 5.11(s, 2H), 4.23 (q, J=7.4 Hz, 2H), 3.62-3.68 (m, 2H), 3.36-3.42 (m, 2H),3.20 (s, 3H), 1.45 (t, J=7.3 Hz, 3H).

HRMS (ESI) calcd for C26H25F4N4O4S [M+H]+: 565.1527, found: 565.1506.

Method E Steps a, c, dN-{3-[4-(2-Amino-pyridin-4-yl)-1-ethyl-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide

[(I)U, R1, R4, R5=H; R3, R6=F; m=2; A=—NHSO2-; R7=2,5-difluorophenyl]

N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzenesulfonamide(123 mg, 0.217 mmol) was dissolved in dry DCM, mCPBA (75 mg, 2 eq) wasadded and the reaction mixture was stirred at room temperature for 3hours. A further addition of mCPBA was made (50 mg) and the mixture wasstirred for 2 more hours. It was then diluted with DCM, washed withsaturated aqueous NaHCO₃ and brine, dried over Na₂SO₄ and evaporated todryness. The crude intermediate N-oxide (130 mg) was dissolved in drytrifluoromethylbenzene (1.5 mL), the solution was cooled to 0° C. andt-butyl amine (0.118 mL 1.12 mmol, 5 eq) was added. Tosylanhydride (150mg, 0.448 mmol, 2 eq) was then added in portions. After 1 h stirring at0° C., further additions of t-butyl amine (0.03 mL, 1.25 eq) andtosylanhydride (40 mg, 0.5 eq) were made and the reaction mixture wasstirred at 0° C. for 30 more minutes. Trifluoroacetic acid (1.5 mL) wasthen added and the mixture was hated to 70° C. and stirred at thistemperature for 1.5 h. The solvent was evaporated and the residue takenup with DCM and water. The aqueous phase was neutralized with 32% aq.NaOH and extracted 3 times with DCM. The combined organic layers werewashed with brine, dried over Na₂SO₄ and evaporated to dryness. Thecrude product was purified by chromatography on silica gel (DCM/MeOH95:5) to give 46 mg ofN-{3-[4-(2-amino-pyridin-4-yl)-1-ethyl-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamideas a white solid.

HPLC (254 nm): R_(t): 5.19 min.

¹H-NMR (401 MHz, DMSO-d6) δ=9.87-11.05 (m, 1H), 8.22 (s, 1H), 7.68 (d,J=5.5 Hz, 1H), 7.51-7.58 (m, 1H), 7.33-7.50 (m, 3H), 7.06-7.21 (m, 1H),6.25 (d, J=0.7 Hz, 1H), 6.02 (dd, J=1.3, 5.3 Hz, 1H), 5.85 (br. s., 2H),4.19 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.3 Hz, 3H).

1. A compound of formula (I):

wherein: m is an integer from 0 to 6; R1 is hydrogen, trichloromethyl,trifluoromethyl, halogen, cyano, OH, OR8, NR9R10, NR21COR22, COOH,COOR11, CONR12R13, or a group optionally substituted selected fromstraight or branched (C₁-C₈) alkyl, (C₂-C₈) alkenyl or (C₂-C₈) alkynyl,(C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkenyl, heterocyclyl, aryl andheteroaryl, wherein: R8 and R11 are each independently a groupoptionally substituted selected from straight or branched (C₁-C₈) alkyl,(C₃-C₈) cycloalkyl, heterocyclyl, aryl and heteroaryl; R9, R10, R12 andR13 the same or different, are each independently hydrogen or a groupoptionally substituted selected from straight or branched (C₁-C₈) alkyl,(C₃-C₈) cycloalkyl, heterocyclyl, aryl and heteroaryl, or taken togetherwith the nitrogen atom to which they are bonded either R9 and R10 aswell as R12 and R13 may form an optionally substituted heterocyclyl orheteroaryl, optionally containing one additional heteroatom orheteroatomic group selected from S, O, N or NH; R21 and R22 the same ordifferent, are each independently hydrogen or a group optionallysubstituted selected from straight or branched (C₁-C₈) alkyl, (C₃-C₈)cycloalkyl, heterocyclyl, aryl and heteroaryl, or taken together withthe atoms to which they are bonded R21 and R22 may form an optionallysubstituted heterocyclyl, optionally containing one additionalheteroatom or heteroatomic group selected from S, O, N or NH; X is —CHor N; R2 is hydrogen, halogen, NR14R15, SR23 or SO₂R23, wherein: R14 andR15 are independently hydrogen or a group optionally substitutedselected from straight or branched (C₁-C₈) alkyl, (C₃-C₈) cycloalkyl,heterocyclyl, aryl and heteroaryl; or taken together with the nitrogenatom to which they are bonded R14 and R15 may form an optionallysubstituted 3 to 8 membered heterocyclyl or heteroaryl, optionallycontaining one additional heteroatom or heteroatomic group selected fromS, O, N or NH; or R14 is hydrogen and R15 is COR16, wherein: R16 isOR17, NR18R19 or a group optionally substituted selected from straightor branched (C₁-C₈) alkyl, (C₂-C₈) alkenyl or (C₂-C₈) alkynyl, (C₃-C₈)cycloalkyl, (C₃-C₈) cylcoalkenyl, heterocyclyl, aryl and heteroaryl,wherein: R17 is a group optionally substituted selected from straight orbranched (C₁-C₈) alkyl, (C₃-C₈) cycloalkyl, heterocyclyl, aryl andheteroaryl; R18 and R19 are each independently a group optionallysubstituted selected from straight or branched (C₁-C₈) alkyl, (C₃-C₈)cycloalkyl, heterocyclyl, aryl and heteroaryl, or taken together withthe nitrogen atom to which they are bonded R18 and R19 may form anoptionally substituted 3 to 8 membered heterocyclyl or heteroaryl,optionally containing one additional heteroatom or heteroatomic groupselected from S, O, N or NH; R23 is a group optionally substitutedselected from straight or branched (C₁-C₈) alkyl, (C₃-C₈) cycloalkyl,heterocyclyl, aryl and heteroaryl, R3, R4, R5 and R6 are eachindependently hydrogen, halogen, trifluoromethyl, trichloromethyl,cyano, OR20 or a group optionally substituted selected from straight orbranched (C₁-C₈) alkyl, and (C₃-C₈) cycloalkyl, wherein: R20 is a groupoptionally substituted selected from straight or branched (C₁-C₈) alkyland (C₃-C₈) cycloalkyl; A is —CON(Y), —CON(Y)O—, —CON(Y)N(Y)—,—CON(Y)SO₂—, —SO₂N(Y)—, —SO₂N(Y)O—, —SO₂N(Y)N(Y)—, —SO₂N(Y)CO—,—SO₂N(Y)CON(Y)—, —SO₂N(Y)SO₂—, —N(Y)CO—, —N(Y)SO₂—, —N(Y)CON(Y)—,—N(Y)CSN(Y)—, —N(Y)CON(Y)N(Y)—, —N(Y)COO—, —N(Y)CON(Y)SO₂—,—N(Y)SO₂N(Y)—, —C(R′R″)CON(Y)—, —C(R′R″)CSN(Y)—, —C(R′R″)CON(Y)O—,—C(R′R″)CON(Y)N(Y)—, —C(R′R″)CON(Y)SO₂—, —C(R′R″)SO₂N(Y)—,—C(R′R″)SO₂N(Y)O—, —C(R′R″)SO₂N(Y)N(Y)—, —C(R′R″)SO₂N(Y)CO—,—C(R′R″)SO₂N(Y)SO₂—, —C(R′R″)N(Y)CO, —C(R′R″)N(Y)SO₂—,—C(R′R″)N(Y)CON(Y)—, —C(R′R″)N(Y)CSN(Y)—, C(R′R″)N(Y)COO—,—C(R′R″)N(Y)SO₂N(Y)— or —N(Y)C(R′R″)—, wherein: Y is hydrogen or anoptionally substituted straight or branched (C₁-C₃) alkyl; and R′ and R″are independently hydrogen or an optionally further substituted straightor branched (C₁-C₆) alkyl, or taken together with the carbon atom towhich they are bonded R′ and R″ may form an optionally substituted(C₃-C₈) cycloalkyl; R7 is hydrogen or an optionally substituted groupselected from straight or branched (C₁-C₈) alkyl, (C₂-C₈) alkenyl, or(C₃-C₈) cycloalkyl, (C₂-C₈) alkynyl, (C₃-C₈) cylcoalkenyl, heterocyclyl,aryl and heteroaryl; and pharmaceutically acceptable salts thereof.
 2. Acompound of formula (I) as defined in claim 1 wherein: m is an integerfrom 0 to
 2. 3. A compound of formula (I) as defined in claim 1 wherein:A is —CON(Y), —CON(Y)O—, —CON(Y)N(Y)—, —CON(Y)SO₂—, —SO₂N(Y)—, —N(Y)CO—,—N(Y)SO₂—, —N(Y)CON(Y)—, —N(Y)CSN(Y)—, —N(Y)COO—, —C(R″ R″)CON(Y)—,—C(R′R″)N(Y)CO, —C(R″R′″)N(Y)CON(Y)—, wherein: Y, R″ and R′″ are asdefined in claim
 1. 4. A compound of formula (I) as defined in claim 1wherein: R1 is hydrogen, trichloromethyl, trifluoromethyl, halogen,cyano, Oil, OR8, NR9R10, CONR12R13, or a group optionally substitutedselected from straight or branched (C₁-C₈) alkyl, (C₂-C₈) alkenyl or(C₂-C₈) alkynyl, (C₃-C₈) cycloalkyl, (C₃-C₈) cycloalkenyl, heterocyclyl,aryl and heteroaryl, wherein: R8, R9, R10, R12 and R13 are as defined inclaim
 1. 5. A compound of formula (I) as defined claim 1, wherein: R1 ishydrogen, trichloromethyl, trifluoromethyl, halogen and cyano.
 6. Acompound of formula (I) as defined in claim 1 wherein: R2 is hydrogen orNR14R15, wherein: R14 and R15 are independently hydrogen or a groupoptionally substituted selected from straight or branched (C₁-C₈) alkyl,(C₃-C₈) cycloalkyl, heterocyclyl, aryl and heteroaryl.
 7. A compound offormula (I) as defined in claim 1 wherein: R3, R4, R5 and R6 are eachindependently hydrogen, halogen, trifluoromethyl, trichloromethyl orcyano.
 8. A compound of formula (I) as defined in claim 1 wherein: R7 isan optionally substituted group selected from straight or branched(C₁-C₈) alkyl, (C₃-C₈) cylcoalkyl, (C₃-C₈) cycloalkenyl, heterocyclyl,aryl and heteroaryl.
 9. A compound of formula (I) or a pharmaceuticallyacceptable salt thereof as defined in claim 1 which is selected from thegroup consisting of:-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,2,5-difluoro-N-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide,N-(4-chloro-phenyl)-3-(4-pyridin-4-yl)-1H-pyrazol-3-yl)-benzamide,N-(4-tert-Butyl-phenyl)-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-benzamide,1-(4-chloro-3-trifluoromethyl-phenyl)-3-{3-[1-(2-fluoro-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-urea,furan-2-sulfonic acid [3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,thiophene-3-sulfonic acid[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,1-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-p-tolyl-urea,1-(4-chloro-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea,1-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,1-[3-(1-cyanomethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,1-{3-[1-(2-amino-pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}-3-(4-trifluoromethyl-phenyl)-urea,1-{3-[1-(2-fluoro-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-3-(4-trifluoromethyl-phenyl)-urea,1-{3-[1-(2-hydroxy-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-3-(4-trifluoromethyl-phenyl)-urea,1-[3-(1-piperidin-4-yl-4-pyridin-4-yl-1′-1-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,N-[3-(4-pyridin-4-yl)-1H-pyrazol-3-yl)-phenyl]-2-(4-trifluoromethyl-phenyl)-acetamide,N-[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyridin-2-yl]-acetamide,N-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-benzenesulfonamide,thiophene-3-sulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,furan-2-sulfonic acid [2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-ye-phenyl]-amide,propane-1-sulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,1-(4-tert-butyl-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea,1-[4-(cyano-dimethyl-methyl)-phenyl]-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea,1-[2-fluoro-5-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,1-(2-fluoro-4-trifluoromethyl-phenyl)-3-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-urea,cyclopropanesulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,2,2,2-trifluoro-ethanesulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,N-[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-C,C,C-trifluoro-methanesulfonamide,cyclohexanesulfonic acid[2,4-difluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-amide,1-[3-(4-pyrimidin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,1-{3-[4-(2-amino-pyrimidin-4-yl)-1H-pyrazol-3-yl]-phenyl}-3-(4-trifluoromethyl-phenyl)-urea,N-[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyrimidin-2-yl]-acetamide,2,5-difluoro-N-[3-(4-pyrimidin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide,N-{3-[4-(2-amino-pyrimidin-4-yl)-1H-pyrazol-3-yl]-phenyl}-2,5-difluoro-benzenesulfonamide,N-(4-{3-[3-(2,5-difluoro-benzenesulfonylamino)-phenyl]-1H-pyrazol-4-yl}-pyrimidin-2-yl)-acetamide,N-[2,4-difluoro-3-(4-pyrimidin-4-yl-1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-benzenesulfonamide,N-{3-[4-(2-amino-pyrimidin-4-yl)-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide,N-(4-{3-[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-1H-pyrazol-4-yl}-pyrimidin-2-yl)-acetamide,N-[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-11′-pyrazol-4-yl)-pyridin-2-yl]-propionamide,N-[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyridin-2-yl]-isobutyramide,cyclopentanecarboxylic acid[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyridin-2-yl]-amide,2-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-N-(4-trifluoromethyl-phenyl)-acetamide,4-hydroxy-N-[4-(3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1H-pyrazol-4-yl)-pyridin-2-yl]-butyramide,N-(4-{3-[3-(2,5-difluoro-benzenesulfonylamino)-phenyl]-1H-pyrazol-4-yl}-pyridin-2-yl)-acetamide,N-(4-{3-[3-(2,5-difluoro-benzenesulfonylamino)-2,6-difluoro-phenyl]-1H-pyrazol-4-yl}-pyridin-2-yl)-acetamide,3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-N-(4-trifluoromethyl-phenyl)-benzamide,4-pyridin-4-yl-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazole-1-carboxylicacid ethyl ester1-[3-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,1-[3-(1-butyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,1-[3-(1-Isobutyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea,N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide,N-[2,4-difluoro-3-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-benzenesulfonamide,N-{2,4-difluoro-3-[4-(2-methylamino-pyridin-4-yl)-1H-pyrazol-3-yl]-phenyl}-2,5-difluoro-benzenesulfonamide,N-{3-[4-(2-ethylamino-pyridin-4-yl)-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide,N-{3-[4-(2-ethylamino-pyrimidin-4-yl)-1H-pyrazol-3-yl]-phenyl}-2,5-difluoro-benzenesulfonamide,N-[2,4-difluoro-3-(1-isobutyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-2,5-difluoro-benzenesulfonamide,N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide,N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide,N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-4-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide,N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide,N-{3-[4-(2-amino-pyrimidin-4-yl)-1-ethyl-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide,N-{2,4-difluoro-3-[1-(2-piperidin-1-yl-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-2,5-difluoro-benzenesulfonamide,N-{2,4-difluoro-3-[1-(2-morpholin-4-yl-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenyl}-2,5-difluoro-benzenesulfonamide,N-(2,4-difluoro-3-{1-[2-(4-methyl-piperazin-1-yl)-ethyl]-4-pyridin-4-yl-1H-pyrazol-3-yl}-phenyl)-2,5-difluoro-benzenesulfonamide,N-{3-[1-(2-dimethylamino-ethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide,(2,5-difluoro-benzyl)-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-amine,4-{3-[3-(2,5-difluoro-benzyloxy)-2,6-difluoro-phenyl]-1-ethyl-1H-pyrazol-4-yl}-pyridineandN-{3-[4-(2-Amino-pyridin-4-yl)-1-ethyl-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide.10. A method for treating a disease caused by and/or associated with aderegulated protein kinase activity which comprises administering to amammal in need thereof an effective amount of a compound of formula (I)as defined in claim
 1. 11. The method according to claim 10 for treatinga disease caused by and/or associated with a deregulated Raf familykinase activity.
 12. The method according to claim 10 wherein thedisease is selected from the group consisting of cancer and cellproliferative disorders.
 13. The method according to claim 12 whereinthe cancer is selected from the group consisting of carcinoma such asbladder, breast, colon, kidney, liver, lung, including small cell lungcancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix,thyroid, prostate, and skin, including squamous cell carcinoma;hematopoietic tumors of lymphoid lineage including leukaemia, acutelymphocitic leukaemia, acute lymphoblastic leukaemia, B-cell lymphoma,T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy celllymphoma and Burkett's lymphoma; hematopoietic tumors of myeloidlineage, including acute and chronic myelogenous leukemias,myelodysplastic syndrome and promyelocytic leukaemia; tumors ofmesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumorsof the central and peripheral nervous system, including astrocytomaneuroblastoma, glioma and schwannomas; other tumors, including melanoma,seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum,keratoxanthoma, thyroid follicular cancer and Kaposi's sarcoma.
 14. Themethod according to claim 12 wherein the cell proliferative disorder isselected from the group consisting of benign prostate hyperplasia,familial adenomatosis polyposis, neurofibromatosis, psoriasis, vascularsmooth cell proliferation associated with atherosclerosis, pulmonaryfibrosis, arthritis, glomerulonephritis and post-surgical stenosis andrestenosis.
 15. The method according to claim 10 further comprisingsubjecting the mammal in need thereof to a radiation therapy orchemotherapy regimen in combination with at least one cytostatic orcytotoxic agent.
 16. The method according to claim 10 wherein the mammalin need thereof is a human.
 17. An in vitro method for inhibiting theRAF family activity which comprises contacting the said receptor with aneffective amount of a compound as defined in claim
 1. 18. The methodaccording to claim 10 which provides tumor angiogenesis and metastasisinhibition.
 19. A pharmaceutical composition comprising atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof, as defined in claim 1, and atleast one pharmaceutically acceptable excipient, carrier and/or diluent.20. A pharmaceutical composition according to claim 19 furthercomprising one or more chemotherapeutic agents.
 21. A product or kitcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof, as defined in claim 1, or pharmaceutical compositionscomprising a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof and at least onepharmaceutically acceptable excipient, carrier and/or diluent, and oneor more chemotherapeutic agents, as a combined preparation forsimultaneous, separate or sequential use in anticancer therapy.
 22. Acompound of formula (I) or a pharmaceutically acceptable salt thereof,as defined in claim 1, for use as a medicament.
 23. (canceled) 24.(canceled)